新型抗生素UDP-3-O-（R-羟基十四酰）-N-乙酰氨基葡糖脱乙酰酶（LpxC）抑制剂的设计、合成及活性研究
|
摘要
研究背景
革兰氏阴性菌耐药及耐药菌感染问题已成为公众健康的最大威胁之一,是21世纪抗感染领域面临的巨大挑战。因此,寻找具有全新抗菌机制和抗菌靶点的新型抗菌药物已迫在眉睫。
在革兰氏阴性菌中,UDP-3-O-(R-羟基十四酰)-N-乙酰氨基葡萄糖脱乙酰化酶(LpxC),是一种锌离子依赖性蛋白水解酶,它催化脂质A生物合成中最关键一步,为革兰阴性菌生存和毒力所必需。此外,LpxC酶在革兰氏阴性菌不同菌株中高度保守,与其它已知锌蛋白酶相比不具有同源性。因此,LpxC作为抗菌新靶点已成为近年来抗菌药物研究中的热点领域,针对这一靶标设计合成抑制剂是当前抗菌药物研究中很有发展前景的一类。
目标化合物的设计、合成及活性筛选
对已有LpxC抑制剂的药效团和定量构效关系总结发现,几乎所有高活性的LpxC抑制剂都具有共同的结构特征即含有与催化活性中心Zn2+螯合的基团(如异羟肟酸等)和与酶的疏水通道之间有效结合的疏水侧链。除上述两个主要的抑制剂结合位点外,还有"UDP binding site"这一结合位点,它对于促进底物与酶的识别和结合非常重要,是当前LpxC抑制剂设计的重要方向之一。在充分调研文献的基础上,本研究以LpxC为靶标,基于LpxC与其抑制剂作用模式,借助计算机辅助药物设计,结合构象限制、电子等排等策略,设计了系列新型的LpxC抑制剂。在合成目标化合物之前,我们利用SYBYL8.0对所设计的化合物进行了对接打分,结果显示大部分化合物分值都接近于甚至超过阳性对照。这说明了我们设计思路的合理性,为我们的研究提供了理论依据。
合成过程中,A系列以L-羟脯氨酸为起始原料,经过系列反应如酯化、Boc保护或磺化、SN2亲核取代、Suzuki偶联反应、缩合反应、Sonogashira Coupling、 Mitsunobu Reaction等合成带有羧酸甲酯结构的目标化合物的前体。B系列以各种L构型氨基酸为起始原料,经过系列反应如Sonogashira Coupling、酯水解、缩合反应、Glaser Coupling等合成带有羧酸甲酯结构的目标化合物的前体。C系列分别以两种光学结构的氯霉胺及D-对甲砜基苯丝氨酸乙酯为起始原料,经过系列反应如Boc保护,羟基的选择性氧化、Sonogashira Coupling、酯水解、缩合反应、Glaser Coupling等合成带有羧酸甲酯结构的目标化合物的前体。D系列由B系列的中间体(S)-2-(4-乙炔基苯甲酰胺基)-4-甲硫基-丁酸甲酯经硫醚氧化成砜或亚砜与Boc保护的乙炔苯胺进行Glaser Coupling合成带有羧酸甲酯结构的目标化合物的前体。最后这些羧酸甲酯前体化合物均通过酯交换转化成异羟肟酸而得到目标化合物。
对所合成的目标化合物进行了初步的生物活性评价,包括最低抑菌浓度MIC的测定,抑菌环试验及体外抑酶活性实验三方面,以期更准确地筛选出高活性的LpxC抑制剂。
结果
所有目标化合物均由'HNMR、HR-MS等方法进行结构确证,经Scifinder等文献检索工具证实,所合成的目标化合物均为新型化合物,未见文献报道。
四系列化合物都表现出对革兰氏阴性菌(E. coil ATCC25922和P. aeruginosa ATCC27853)的选择性抑菌作用,对两株革兰氏阳性菌(S.A. ATCC25923和MRS.A. ATCC29213)则无明显抑菌作用。通过上述两株革兰氏阴性菌株的初筛,对活性较好的化合物进行了三株耐药菌株(E. coil MDR、P. aeruginosa MDR和E. cloacae MDR)的MIC测定。部分目标化合物的抑菌活性与阳性对照LPC009相比略弱。对活性最好的化合物D1和D2还进行了大肠杆菌野生型菌株(E. coilW3110)和membrane-compromised strain (E. coil CMR300)的MIC的测定,此部分工作由Duke University完成。
此外,对活性最好的两个化合物D1和D2,进行了两株细菌ATCC25922和P. aeruginosa ATCC27853)的抑菌环试验。结果显示测试化合物与阳性对照药LPC009、Levofloxacin、Claforan抑菌活性相当。
LpxC抑制剂的酶活测定方法条件比较苛刻,故根据上述MIC的测定结果,选取抗菌活性最好的两个化合物D1和D2进行EcLpxC的酶活测定,此部分工作由Duke University完成,活性结果表明所测两个化合物与阳性对照LPC028的抑酶活性相当,可作为抗革兰阴性菌先导进行深入研究。
结论
本研究基于LpxC的晶体结构及抑制剂与LpxC的作用模式,设计、合成了四系列新型的LpxC抑制剂,在体外表现出广谱的抗革兰氏阴性菌活性及较好的抑酶活性。这些化合物是很有研究前景的先导化合物,对具有全新作用机制的新型抗生素的研发有着积极的指导意义。
Background
The rapid increase of infections by Gram-negative pathogens along with the emergence of drug-resistant bacterial strains, posing the serious threat to the public health, is the great challenge in21century and demands the development of novel antibiotics directed against the previously unexploited targets.
One of the promising targets in Gram-negative bacteria is the zinc-dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC catalyzes the first committed, second overall step in the biosynthetic pathway of lipid A, which is essential for the bacterial viability and toxicity. Additionally, LpxC is highly conserved among Gram-negative bacteria and shares no sequence homology with any other known zinc-metalloenzymes. Thus LpxC has become an attractive target for the structure-based drug design, and research on LpxC inhibitors is a very promising strategy in the development of current antibiotic therapy for Gram-negative bacteria.
Design、synthesis and activity evaluation of target compounds
Currently identified LpxC shared the same structural characters and almost all of the potent inhibitors contain a hydroxamate group for chelating the catalytic Zn2+and a side chain for effectively interacting with the hydrophobic tunnel. Based on the LpxC crystal structures and the binding mode of the known LpxC inhibitors in complex with LpxC, we designed4series of novel compounds as LpxC inhibitors with the strategies of CADD, conformational restriction and biosiostere. Before synthesizing the designed compounds, we docked our compounds with EcLpxC via FlexX of sybyl8.0. The result showed that almost all of the compounds had similar or higher score than the positive control, which, to some extent, ensured the rationality of our design strategy and supplied basement for our study.
During the synthesis of series A, all the compounds designed were synthesized using L-hydroxyproline as starting material through a reaction sequence including esterification, Boc-protection or sulfonylation, SN2nucleophilic substitution, Suzuki couplingcon, condensation, Sonogashira coupling, mitsunobu reaction to obtain the key intermediate. During the synthesis of series B, all the compounds designed were synthesized using various L amino acids as starting material through a reaction sequence including Sonogashira coupling, hydrolysis, condensation, Galaser coupling to obtain the key intermediate. During the synthesis of series C, all the compounds designed were synthesized using (S)-methyl2-(4-ethynylbenzamido)-4-(methylthio)-butanoate as starting material through a reaction sequence including oxidation, Galaser coupling to obtain the key intermediate. The methyl ester groups of all the former compounds were converted to hydroxymate group to obtain the target compounds.
Additionally, aiming for high activity compounds, preliminary activity assay was also carried out in vitro including MIC assay, antibacterial annulus and anti-LpxC assay.
Results
In this research, all target compounds were obtained and identified by1H-NMR and HRMS spectra. Literature retrieval proved that all the compounds were new and not reported.
In MIC assay, the results showed that four series of these compounds exhibited highly selective antibacterial activity against Gram-negative bacteria (E.coil ATCC 25922and P. aeruginosa ATCC27853) as compared with Gram-positive bacteria (S.A. ATCC25923和MRS.A. ATCC29213). Some potent compounds were also assayed for their antibacterial activities against E.coil (MDR), P. aeruginosa (MDR) and E.cloacae (MDR). Among them, a few target compounds showed slightly lower activity compared with positive control. While, the most potent compounds D1and D2were chosen to be assayed for their antibacterial activities against E. coil W3110(wild-type strain) and E. coil CMR300(membrane-compromised strain), which was finished in Duke University.
Compounds D1and D2were also assayed for their antibacterial annulus against Ecoil ATCC25922and P. aeruginosa ATCC27853. The results showed that these two compounds was comparable to the positive control LPC009, Levofloxacin, Claforan towards these two strains.
Additionally, the most potent compounds Dl and D2were also chosen to be carried out anti-LpxC assay. The results showed that these two compounds was comparable to the positive control LPC028towards EcLpxC and they can be researched deeply in the future work.
Conclusions
In conclusion, based on the crystal structure of LpxC and the binding mode of the known LpxC inhibitors with the enzyme, we designed and synthesized four series of the target compounds. Preliminary antibacterial activities assay and enzyme activity assay showed most compounds possess potential activity. These compounds are promising lead compounds for developing new LpxC inhibitors as novel antibiotic.
革兰氏阴性菌耐药及耐药菌感染问题已成为公众健康的最大威胁之一,是21世纪抗感染领域面临的巨大挑战。因此,寻找具有全新抗菌机制和抗菌靶点的新型抗菌药物已迫在眉睫。
在革兰氏阴性菌中,UDP-3-O-(R-羟基十四酰)-N-乙酰氨基葡萄糖脱乙酰化酶(LpxC),是一种锌离子依赖性蛋白水解酶,它催化脂质A生物合成中最关键一步,为革兰阴性菌生存和毒力所必需。此外,LpxC酶在革兰氏阴性菌不同菌株中高度保守,与其它已知锌蛋白酶相比不具有同源性。因此,LpxC作为抗菌新靶点已成为近年来抗菌药物研究中的热点领域,针对这一靶标设计合成抑制剂是当前抗菌药物研究中很有发展前景的一类。
目标化合物的设计、合成及活性筛选
对已有LpxC抑制剂的药效团和定量构效关系总结发现,几乎所有高活性的LpxC抑制剂都具有共同的结构特征即含有与催化活性中心Zn2+螯合的基团(如异羟肟酸等)和与酶的疏水通道之间有效结合的疏水侧链。除上述两个主要的抑制剂结合位点外,还有"UDP binding site"这一结合位点,它对于促进底物与酶的识别和结合非常重要,是当前LpxC抑制剂设计的重要方向之一。在充分调研文献的基础上,本研究以LpxC为靶标,基于LpxC与其抑制剂作用模式,借助计算机辅助药物设计,结合构象限制、电子等排等策略,设计了系列新型的LpxC抑制剂。在合成目标化合物之前,我们利用SYBYL8.0对所设计的化合物进行了对接打分,结果显示大部分化合物分值都接近于甚至超过阳性对照。这说明了我们设计思路的合理性,为我们的研究提供了理论依据。
合成过程中,A系列以L-羟脯氨酸为起始原料,经过系列反应如酯化、Boc保护或磺化、SN2亲核取代、Suzuki偶联反应、缩合反应、Sonogashira Coupling、 Mitsunobu Reaction等合成带有羧酸甲酯结构的目标化合物的前体。B系列以各种L构型氨基酸为起始原料,经过系列反应如Sonogashira Coupling、酯水解、缩合反应、Glaser Coupling等合成带有羧酸甲酯结构的目标化合物的前体。C系列分别以两种光学结构的氯霉胺及D-对甲砜基苯丝氨酸乙酯为起始原料,经过系列反应如Boc保护,羟基的选择性氧化、Sonogashira Coupling、酯水解、缩合反应、Glaser Coupling等合成带有羧酸甲酯结构的目标化合物的前体。D系列由B系列的中间体(S)-2-(4-乙炔基苯甲酰胺基)-4-甲硫基-丁酸甲酯经硫醚氧化成砜或亚砜与Boc保护的乙炔苯胺进行Glaser Coupling合成带有羧酸甲酯结构的目标化合物的前体。最后这些羧酸甲酯前体化合物均通过酯交换转化成异羟肟酸而得到目标化合物。
对所合成的目标化合物进行了初步的生物活性评价,包括最低抑菌浓度MIC的测定,抑菌环试验及体外抑酶活性实验三方面,以期更准确地筛选出高活性的LpxC抑制剂。
结果
所有目标化合物均由'HNMR、HR-MS等方法进行结构确证,经Scifinder等文献检索工具证实,所合成的目标化合物均为新型化合物,未见文献报道。
四系列化合物都表现出对革兰氏阴性菌(E. coil ATCC25922和P. aeruginosa ATCC27853)的选择性抑菌作用,对两株革兰氏阳性菌(S.A. ATCC25923和MRS.A. ATCC29213)则无明显抑菌作用。通过上述两株革兰氏阴性菌株的初筛,对活性较好的化合物进行了三株耐药菌株(E. coil MDR、P. aeruginosa MDR和E. cloacae MDR)的MIC测定。部分目标化合物的抑菌活性与阳性对照LPC009相比略弱。对活性最好的化合物D1和D2还进行了大肠杆菌野生型菌株(E. coilW3110)和membrane-compromised strain (E. coil CMR300)的MIC的测定,此部分工作由Duke University完成。
此外,对活性最好的两个化合物D1和D2,进行了两株细菌ATCC25922和P. aeruginosa ATCC27853)的抑菌环试验。结果显示测试化合物与阳性对照药LPC009、Levofloxacin、Claforan抑菌活性相当。
LpxC抑制剂的酶活测定方法条件比较苛刻,故根据上述MIC的测定结果,选取抗菌活性最好的两个化合物D1和D2进行EcLpxC的酶活测定,此部分工作由Duke University完成,活性结果表明所测两个化合物与阳性对照LPC028的抑酶活性相当,可作为抗革兰阴性菌先导进行深入研究。
结论
本研究基于LpxC的晶体结构及抑制剂与LpxC的作用模式,设计、合成了四系列新型的LpxC抑制剂,在体外表现出广谱的抗革兰氏阴性菌活性及较好的抑酶活性。这些化合物是很有研究前景的先导化合物,对具有全新作用机制的新型抗生素的研发有着积极的指导意义。
Background
The rapid increase of infections by Gram-negative pathogens along with the emergence of drug-resistant bacterial strains, posing the serious threat to the public health, is the great challenge in21century and demands the development of novel antibiotics directed against the previously unexploited targets.
One of the promising targets in Gram-negative bacteria is the zinc-dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC catalyzes the first committed, second overall step in the biosynthetic pathway of lipid A, which is essential for the bacterial viability and toxicity. Additionally, LpxC is highly conserved among Gram-negative bacteria and shares no sequence homology with any other known zinc-metalloenzymes. Thus LpxC has become an attractive target for the structure-based drug design, and research on LpxC inhibitors is a very promising strategy in the development of current antibiotic therapy for Gram-negative bacteria.
Design、synthesis and activity evaluation of target compounds
Currently identified LpxC shared the same structural characters and almost all of the potent inhibitors contain a hydroxamate group for chelating the catalytic Zn2+and a side chain for effectively interacting with the hydrophobic tunnel. Based on the LpxC crystal structures and the binding mode of the known LpxC inhibitors in complex with LpxC, we designed4series of novel compounds as LpxC inhibitors with the strategies of CADD, conformational restriction and biosiostere. Before synthesizing the designed compounds, we docked our compounds with EcLpxC via FlexX of sybyl8.0. The result showed that almost all of the compounds had similar or higher score than the positive control, which, to some extent, ensured the rationality of our design strategy and supplied basement for our study.
During the synthesis of series A, all the compounds designed were synthesized using L-hydroxyproline as starting material through a reaction sequence including esterification, Boc-protection or sulfonylation, SN2nucleophilic substitution, Suzuki couplingcon, condensation, Sonogashira coupling, mitsunobu reaction to obtain the key intermediate. During the synthesis of series B, all the compounds designed were synthesized using various L amino acids as starting material through a reaction sequence including Sonogashira coupling, hydrolysis, condensation, Galaser coupling to obtain the key intermediate. During the synthesis of series C, all the compounds designed were synthesized using (S)-methyl2-(4-ethynylbenzamido)-4-(methylthio)-butanoate as starting material through a reaction sequence including oxidation, Galaser coupling to obtain the key intermediate. The methyl ester groups of all the former compounds were converted to hydroxymate group to obtain the target compounds.
Additionally, aiming for high activity compounds, preliminary activity assay was also carried out in vitro including MIC assay, antibacterial annulus and anti-LpxC assay.
Results
In this research, all target compounds were obtained and identified by1H-NMR and HRMS spectra. Literature retrieval proved that all the compounds were new and not reported.
In MIC assay, the results showed that four series of these compounds exhibited highly selective antibacterial activity against Gram-negative bacteria (E.coil ATCC 25922and P. aeruginosa ATCC27853) as compared with Gram-positive bacteria (S.A. ATCC25923和MRS.A. ATCC29213). Some potent compounds were also assayed for their antibacterial activities against E.coil (MDR), P. aeruginosa (MDR) and E.cloacae (MDR). Among them, a few target compounds showed slightly lower activity compared with positive control. While, the most potent compounds D1and D2were chosen to be assayed for their antibacterial activities against E. coil W3110(wild-type strain) and E. coil CMR300(membrane-compromised strain), which was finished in Duke University.
Compounds D1and D2were also assayed for their antibacterial annulus against Ecoil ATCC25922and P. aeruginosa ATCC27853. The results showed that these two compounds was comparable to the positive control LPC009, Levofloxacin, Claforan towards these two strains.
Additionally, the most potent compounds Dl and D2were also chosen to be carried out anti-LpxC assay. The results showed that these two compounds was comparable to the positive control LPC028towards EcLpxC and they can be researched deeply in the future work.
Conclusions
In conclusion, based on the crystal structure of LpxC and the binding mode of the known LpxC inhibitors with the enzyme, we designed and synthesized four series of the target compounds. Preliminary antibacterial activities assay and enzyme activity assay showed most compounds possess potential activity. These compounds are promising lead compounds for developing new LpxC inhibitors as novel antibiotic.
引文
1. Kronenberger, C. B., Hoffman, R. E., Lezotte, D. C., et al. Invasive penicillin-resistant pneumococcal infections:a prevalence and historical cohort study. Emerging Infectious Diseases,1996,2(2):121-124.
2.李凡、徐志凯主编,医学微生物学(第八版)人民卫生出版社，2013.
3. Kumarasamy, K.K., Toleman, M.A., Walsh, T.R., et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK:a molecular, biological, and epidemiological study. The Lancet infectious diseases,2010.10(9):597-602.
4. Hammerum, A.M., Toleman, M.A., Hansen, F., et al. Global spread of New Delhi metallo-β-lactamase 1. The Lancet infectious diseases,2010.10(12):829-830.
5.王媛媛，聂青和.肠出血性大肠杆菌O-104：H4型感染.中国实用内科杂志，2011,31(8)：616-618.
6.郑虎(主编),药物化学(第六版).人民卫生出版社，2008.
7.杨宝峰 主编 药理学 (第八版).人民卫生出版社，2013.
8. Clatworthy, A.E., E. Pierson, and D.T. Hung. Targeting virulence:a new paradigm for antimicrobial therapy. Nature chemical biology,2007.3(9):541-548.
9. Nikaido, H. and Vaara, M.. Molecular basis of bacterial outer membrane permeability. Microbiol Rev,1985,49(1):1-32.
10. Vaara, M.. Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria. Antimicrobial Agents and Chemotherapy, 1993,37(2):354-356.
11. Cock, H.D., Brandenburg, K., Wiese, A., et al. Non-lamellar structure and negative charges of lipopolysaccharides required for efficient folding of outer membrane protein PhoE of Escherichia coli. Journal of Biological Chemistry,1999.274(8):5114-5119.
12. Raetz, C. R. and Whitfield, C.. Lipopolysaccharide endotxins. Annual review of biochemistry, 2002,71(1):635-700.
13. Nikaido, H.. Molecular basis of bacterial outer membrane permeability revisited. Microbiology and Molecular Biology Reviews,2003,67(4):593-656.
14. Raetz, C. R.. Bacterial endotoxins:extraordinary lipids that activate eucaryotic signal transduction. Journal of Bacteriology,1993,175(18):5745-5743.
15. Vuorio, R. and Vaara M.. The lipid A biosynthesis mutation lpxA2 of Escherichia coli results in drastic antibiotic supersusceptibility. Antimicrobial Agents and Chemotherapy,1992,36(4): 826-829.
16. Anderson, M.S., C.E. Bulawa, and C. Raetz, The biosynthesis of gram-negative endotoxin. Formation of lipid A precursors from UDP-GlcNAc in extracts of Escherichia coli. Journal of Biological Chemistry,1985.260(29):15536-15541.
17. Anderson, M.S. and C. Raetz, Biosynthesis of lipid A precursors in Escherichia coli. A cytoplasmic acyltransferase that converts UDP-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)-N-acetyl glucosamine. Journal of Biological Chemistry, 1987.262(11):5159-5169.
18. Anderson, M. S., Bull, H. G., Galloway, S. M., et al. UDP-Nacetylglucosamine acyltransferase of Escherichia coli:The first step of endotoxin biosynthesis is thermodynamically unfavorable, J. Biol. Chem.,1993,268(26),19858-19865.
19. Wyckoflf, T.J.O., C.R.H. Raetz, and J.E. Jackman, Antibacterial and anti-inflammatory agents that target endotoxin. Trends in microbiology,1998.6(4):154-159.
20. White, R. J., Margolis, P. S., Trias, J., and Yuan, Z. Targeting metalloenzymes:A strategy that works. Curr. Opin. Pharmacol,2003,3(5):502-507.
21. Sorensen, P.G., Lutkenhaus, J., Young, K., et al. Regulation of UDP-3-O-[R-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase in Escherichia coli. The second enzymatic step of lipid a biosynthesis. J. Biol. Chem.,1996,271(42),25898-905.
22. Ogura, T., Inoue, K., Tatsuta, T, et al. Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli. Mol. Microbiol,1999,31(3):833-844.
23. Fiihrer, F., Langklotz, S. and Narberhaus, F. The C-terminal end of LpxC is required for degradation by the FtsH protease. Molecular Microbiology,2006,59(3):1025-1036.
24. Stover, C. K., Pham, X. Q., Erwin, A. L., et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature,2000,406(6799),959-964.
25. Blattner, F. R., Plunkett, G., Bloch, C. A., et al. The complete genome sequence of Escherichia coli K-12. Science,1997,277(5331):1453-1474.
26. Whittington, D. A., et al. Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis. PNAS,2003,100(14):8146-8150.
27. Coggins, B. E., Li, X. C., McClerren, A. L., et al. Structure of the LpxC deacetylase with a bound substrate-analog inhibitor. Nature Structural Biology,2003,10(8):645-651.
28. Coggins, B. E., McClerren, A. L., Jiang, L., et al. Refined solution structure of the LpxC-TU-514 complex and pKa analysis of an active site histidine:insights into the mechanism and inhibitor design. Biochemistry,2005,44(4):1114-1126.
29. Brab, A. W., Jiang, L., Raetz, C. R. et al. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090:Time-dependent inhibition and specificity in ligand binding. PNAS, 2007,104(47):18433-18438.
30. Mochalkin, I., Knafels, J. D. and Lightle, S.. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor. Protein Science,2008,17(3): 450-457.
31. Gennadios, H. and Christianson, D. W.. Binding of uridine 5'-diphosphate in the "basic patch" of the zinc deacetylase LpxC and implications for substrate binding. Biochemistry,2006, 45(51):15216-15223.
32. Brab, A. W. and Zou, P.. Mechanism and inhibition of LpxC:an essential zinc-dependent deacetylase of bacterial Lipid A synthesis. Curr. Pharm. Bio.,2008,9:9-15.
33. Buetow, L., Dawson, A. and Hunter W. N. The nucleotide-binding site of Aquifex aeolicus LpxC. Structural Biology And Crystallization Communications,2006,62(11):1082-1086.
34. Hernick, M., et al. UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase functions through a general acid-base catalyst pair mechanism. Journal of Biological Chemistry,2005,280(17):16969-16978.
35. McClerren, A. L., Zou, P., Guan, Z. Q., et al. Kinetic analysis of the zinc-dependent deacetylase in the Lipid A biosynthetic pathway. Biochemistry,2005,44(4):1106-1113.
36. Hernick, M. and Fierke, C. A.. Zinc hydrolases:the mechanisms of zinc-dependent deacetylases. Arch. Biochem. Biophys.,2005,433(1):71-84.
37. Gennadios, H., et al. Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase. Biochemistry,2006,45(26):7940-7948.
38. Zhang, J., Zhang, L., Li, X., Xu, W. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) Inhibitors:A New Class of Antibacterial Agents. Curr. Med. Chem., 2012,19,2038-2050.
39. Onishi, R. H., Pelak, B. A., Gerckens, L. S., et al.Antibacterial agents that inhibit Lipid A biosynthesis. Science,1996,274(5289):980-982.
40. Chen, M. H., Steiner, M. G., Laszlo, S. E., et al. Carbohydroxamido-oxazolidines: antibacterial agents that target lipid A biosynthesis. Bioorganic & medicinal chemistry Letters, 1999,9(3):313-318.
41. Jackman, J. E., Fierke, C. A., Tumey, L. N., et al. Antibacterial agents that target lipid A biosynthesis in Gram-negative bacteria. Journal of Biological Chemistry,2000,275(15): 11002-11009.
42. Mdluli, K. E., Witte, P. R., Kline, T., et al. Molecular validation of LpxC as an antibacterial drug target in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy,2006,50(6): 2178-2184.
43. Kline, T., Anderson, N. H., Harwood, E. A., et al. Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC. J. Med. Chem,2002,45(14):3112-3129.
44. Pirrung, M. C., Tumey, L. N., Raetz, C. R., et al. Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC):isoxazoline zinc amidase inhibitors bearing diverse metal binding groups. J. Med. Chem,2002,45(19):4359-4370.
45. Pirrung, M. C., Tumey, L. N., McClerren, A. L., et al. High-Throughput Catch-and-Release Synthesis of Oxazoline Hydroxamates. Structure-activity relationships in novel inhibitors of Escherichia coli LpxC:in vitro enzyme inhibition and antibacterial properties. J. Am. Chem. Soc,2003,125(6):1575-1586.
46. Clements, J. M., Coiqanard, F., Johnson, I., et al. Antibacterial activities and characterization of novel intibitors of LpxC. Antimicrob. Agents. Chemother.,2002,46(9):1793-1799.
47. Anderson, N. H., Bowman, J., Erwin, A., et al. Antibacterial agents. WO2004062601.2004.
48. McClerren, A. L., Endsly, S., Bowman, J. L., et al. A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of Lipid A biosynthesis with antibiotic activity comparable to Ciprofloxacin. Biochemistry,2005,44(50):16574-16583.
49. Barb, A. W., McClerren, A. L., Snehelatha K., et al. Inhibition of Lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry,2007, 46(12):3793-3802.
50. Cole, K. E., Gattis, S. G., Angell, H. D., et al. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090. Biochemistry,2011,50(2):258-265.
51. Lee, C. J., Liang, X. F., Chen X., et al. Species-specific and inhibitor-dependent conformations of LpxC:implications for antibiotic design. Chemistry & Biology,2010,18(1): 38-47.
52. Liang, X. F., Lee, C. J., Chen X., et al. Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem.,2011,19(2):852-860.
53. Liang, X. F., Lee, C. J., Zhao J. S., et al. Syntheses, structures and antibiotic activities of aryl-substituted LpxC inhibitors.J. Med. Chem.,2013,56(17):6954-66.
54. Brown, M. F., Reilly, U., Abramite, J. A., et al. Potent inhibitors of LpxC for the treatment of Gram-negative infections. J. Med. Chem.,2012,55(2):914-923.
55. Montgomery, J. I., Brown, M. F., Reilly, U., et al. Pyridone methylsulfone hydroxymate LpxC inhibitors for the treatment of serious Gram-negative infections. J. Med. Chem.,2012,55(4): 1662-1670.
56. Loppenberg, M., Miiller, H., Pulina, C., et al. Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors. Org. Biol. Chem.,2013,11(36):6056-70.
57. Szermerski, M., Melesina, J., Wichapong, K., et al. Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors. Bioorg. Med. Chem.,2014,22(3):1016-1028.
58. Mansoor, U. F., Reddy, P., Adulla, P., et al. Hydantoin derivatives useful as antibacterial agents. WO 2008/027466 Al.
59. Cuny, G. D.. A new class of UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections:PCT application WO 2008027466. Expert Opin. Then Patents,2009,19(6):893-899.
60. Brab, A. W., Leavy, T. M., Robins, L. I., et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry,2009,48(14):3068-3077.
61. Shin, H., Gennadios, H. A., Whittington, D. A., et al. Amphipathic benzoic acid derivatives: Synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC. Bioorg. Med. Chem.,2007,15(7):2617-2623.
1. Brab, A. W., Leavy, T. M., Robins, L. I., et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry,2009,48(14):3068-3077.
2.陈凯先,等。计算机辅助药物设计：原理、方法及应用。上海科学技术出版社,2000.
3.徐筱杰,等。计算机辅助药物分子设计。化学工业出版社,2004。
4.徐文方,等。药物设计学。人民卫生出版社,2007。
5. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr. Med. Chem.2008; 15(4):368-73.
6. Clements, J. M., Coiqanard, F., Johnson, I., et al. Antibacterial activities and characterization of novel intibitors of LpxC. Antimicrob. Agents. Chemother.,2002,46(9):1793-1799.
7. Ehrlieh, J., Bartz, Q. R., Smith, R.M., Joslyn, D.A., Burkholder, P.R. Chloromyeetin, a new antibiotic from a soil actinomycete. Scienee,1947,106,417.
8. Shatilo, V.A., Zaritskii, A.M., Kudrya. T.N., Shtepanek, A.S. Effect of 1-(p-nitrophenyl)-2-amino-1,3-propanediol and β-chloroethyl-phosphonic acid derivatives on growth of enterobacteria. Mikrobiologicheskii Zhurnal,1984,46(4):39-42.
9. Drainas, D., Petros, M., Coutsogeorgopoulos, C. Aminoaecyl analogs of chloramphenicol: examination of the kinetics of inhibition of peptide bond formation. J. Med. Chem.,1993, 36(23):3542-3545.
10. Liang, X. F., Lee, C. J., Chen X., et al.Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem.,2011,19(2):852-860.
1. Leadbeater, N.E., Macro, M.. Ligand-free Palladium catalysis of the suzuki reaction in water using microwave heating. Org. lett.,2002,4(17):2973-2976.
2. Shirakawa, E., Kitabata, T., Otsuka, H., Tsuchimoto, T.. A simple catalust system for the palladium-catalyzed coupling of aryl halides with terminal alkynes. Tetrahedron,2005,61, 9878-9885.
3. Percec, V., Rudick, J.G., Peterca, M., et al.Thermoreversible cis-cisoidal to cis-transoidal isomerization of helical dendronized polyphenylacetylenes. J. Am. Chem. Soc.,2005, 127(43):15257-64.
4. Mohamed Ahmed, M.S., Mori, A.. Sonogashira coupling with aqueous ammonia directed to the synthesis of azotolane derivatives. Tetrohedron,2004,60,9977-9982.
5. Vasilevsky, S.F., Klyatskaya, S.V., Elguero, J.. One-pot synthesis of monosubstituted aryl(hetaryl)acetylenes by direct introduction fo the CCH residue into arenes and hetarenes. Tetrohedron,2004,60,6685-6688.
6. Nicolaou, K. C., Zipkin R. E., Petasis, N. A.. The endiandric acid cascade. Electrocyclizations in organic synthesis.4. Biomimetic approach to endiandric acids A-G. Total synthesis and thermal studies. J. Am. Chem. Soc.,1982,104(20):5558-5560.
7. Jordis U, Sauter F, Siddiqi S M. Synthesis of (1S,4S)-2-thia-5-azabicyclo[2.2.1] heptane. Indian. J. Chem.,1989,28(B):294-6.
8. Catherine, J. L., Jerome, D., Anna, Q., et al. Preparation of pyrrolidine derivatives as oxytocin antagonists. WO 2004005249 Al 20040115.
9. Karoyan, P., Chassaing, G. Asymmetric synthesis of 3-alkyl substituted prolines by alkylation of a chiral sulfone. Tetrohedron Lett.,2002,43,1211-1223.
10. Bemardes, G.J.L., Chalker, J.M., Errey, J.C., Davis, B.G. Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces:versatile and switchable access to functionalized proteins. J. Am. Chem. Soc.,2008,130,5052-5053.
11. Hlavacek J, Bennettova B, Barth T, Tykva R. Synthesis, radiolabeling and biological activity of peptide oostatic hormone and its analogues. J. Pept. Res.,1997,50(3):15-158.
1. Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically: Approved Standard.{NCCLS document M7-A7),2006.
2. Jackman, J.E., Raetz, C.R., Fierke, C.A.. Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site. Biochemistry,2001,40(2):514-23.
3. Liang, X.F., Lee, C. J., Zhao, J.S., Toone, E.J., Zhou, P.. Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. J. Med. Chem.,2013,56(17):6954-66.
1. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation. Cell.1991; 64:327-335.
2. Stetler-Stevenson WG. Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol.1993; 9:541-573.
3. Sato H, Takino T, Okada Y. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 1994; 370:61-65.
4. Rundhaug, J. E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med.2005,9(2), 267-285.
5. Sounni NE, Janssen M, Foidart JM, Noel A. Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. Matrix Biol.2003; 22 (1):55-61.
6. Hideaki N, Woessner JF Jr. Matrix metalloproteinases. J. Biol. Chem.1999; 274(31): 21491-21494.
7. Neri M, Baaden M, Carnevale V, Anselmi C, Maritan A, Carloni P. Microseconds dynamics simulations of the outer-membrane protease T. Biophys 2008; 94 (1):71-78.
8. Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl Cancer Inst.1997; 89:1260-1270.
9. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. Engl. J. Med.1995; 333:1757-1763.
10. Mira E, Manes S, Lacalle RA, et al. Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology 1999; 140:1657-1664.
11. Martin DC, Fowlies JL, Babic B, et al. Insulin-like growth factor Ⅱ signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J. Cell Biol.1999; 146:881-892.
12. Manes S, Mira E, Barbacid MM, et al. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J. Biol. Chem.1997; 272:25706-25712.
13. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res.1998; 58:1135-1139.
14. Angelo V, Domenico R, Marco P, et al. Blood.1999; 93(9):3064-3073.
15. Ray JM; Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J.1994; 7 (11):2062-72.
16. O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell.1994; 79 (2): 315-28.
17. Giannelli G; Falk-Marzillier J; Schiraldi O; Stetler-Stevenson WG; Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science.1997; 277(5323): 225-8.
18. Kontogiorgis CA, Papaioannou P, Hadjipavlou L DJ. Matrix metalloproteinase inhibitors:a review on pharmacophore mapping and (Q)SARs results. Curr. Med. Chem.2005; 12(3): 339-55.
19. Kugler A. Matrix metalloproteinases and their inhibitors. Anticancer Res.1999; 19(2C): 1589-92.
20. MacDougall JR; Bani MR; Lin Y; Muschel RJ; Kerbel RS.'Proteolytic switching':opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression. Br. J. Cancer 1999; 80(3-4): 504-12.
21. Nagase H; Woessner JF Jr. Matrix metalloproteinases. J. Biol. Chem.1999; 274 (31): 21491-4.
22. Strongin AY; Collier I; Bannikov G; Marmer BL; Grant GA; Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem.1995; 270 (10):5331-8.
23. Caterina J, Shi J, Krakora S, et al. Isolation, characterization, and chromosomal location of the mouse enamelysin gene. Genomics 1999; 62(2):308-11.
24. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res.1998; 58(6):1135-9.
25. Suemitsu R, Yoshino I, Tomiyasu M, et al. Serum tissue inhibitors of metalloproteinase-1 and-2 in patients with non-small cell lung cancer. Surg. Today 2004; 34 (11):896-901.
26. Nagel H, Laskawi R, Wahlers A, Hemmerlein B. Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1,-2, and-3 in benign and malignant tumours of the salivary gland. Histopathology 2004; 44 (3):222-31.
27. Peterson JT. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev 2004; 9(1):63-79.
28. Annabi B, Lachambre M P, Bousquet-Gagnon N, Page M,Gingras D, Beliveau R. Green tea polyphenol (-)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MTl-MMP-driven migration in glioblastoma cells. Biochim. Biophys. Acta.2002; 1542:209-220.
29. Garbisa S, Sartor L, Biggin S, Salvato B, Benelli R, Albini A.Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate. Cancer.2001; 91:822-832.
30. Oneda H, Shiihara M, Inouye K. Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin). Biochem.2003; 133 (5):571-576.
31. Mannello F. Natural bio-drug as matrix metalloproteinase inhibitors:new perspectives on the horizon? Recent Patents on Anti-Cancer Drug Discovery.2006; 1:91-103.
32. Park WH, Kim SH, Kim CH. A new matrix metalloproteinase-9 inhibitor 3,4-dihydroxycinamic acid(caffeic acid) from methanol extract of Eunonymus alatus: isolation and structure determination. Toxicology.2005; 207(3):383-90.
33. Sartor L, Pezzato E, Dell'Aica Ⅰ, Caniato R, Biggin S, Garbisa S.Inhibition of matrix-proteases by polyphenols:chemical insights for anti-inflammatory and anti-invasion drug design. Biochemical Pharmacology.2002; 64:22-237.
34. Puerta, DT, Lewis JA, Cohen SM. New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups. J. Am. Chem. Soc.2004; 126:8388-8389.
35. Puerta DT, Griffin MO, Cohen, SM, et al. Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors:potency, toxicity, and reactivity. J. Biol. Inorg. Chem.2006; 11:131-138.
36. Ikezoe T, Chen SS, Tong XJ, et al. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int. J. Oncol.2003; 23(4):1187-1193.
37.吴婕,袁守军,杨德宣,田增月。冬凌草甲素抑制BGC823细胞的生长及MMP-2, MMP-9的表达。解放军药学学报2007；23(5)：344-347.
38. Breuer E, Frant J, Reich R. Recent non-hydroxamate matrix metalloproteinase inhibitors. Expert Opin. Then Pat.2005; 15(3):253-269.
39. Fujita M, Nakao Y, Matsunaga S, et al. Ageladine A:an antiangiongenic matrix metalloproteinase inhibitor from the marine sponge agelas nakamurai. J. Am. Chem. Soc.2003; 125(51):15700-15701.
40. Giavazzi R, Garofalo A, Ferri C, et al. A synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts. Clin. Cancer Res.1998; 4(4):985-92.
41. Prontera C, Mariani B, Rossi C, Poggi A, Rotilio D. Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. Int. J. Cancer.1999; 81 (5):761-6.
42. Macaulay VM, O'Byrne KJ, Saunders MP, et al. Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin. Cancer Res.1999; 5(3):513-20.
43. Wojtowicz-Praga S, Torri J, Johnson M, et al. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J. Clin. Oncol.1998; 16(6):2150-6.
44. Primrose JN, Bleiberg H, Daniel F, et al. Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen. Br J. Cancer 1999; 79(3-4):509-14.
45. Steward WP. Marimastat (BB2516):current status of development. Cancer Chemother Pharmacol.1999; 43:56-60.
46. Peterson JT. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev.2004; 9(1):63-79.
47. Shalinsky DR, Brekken J, Zou H, et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann.N Y Acad Sci.1999; 878:236-70.
48. Shalinsky DR, Brekken J, Zou H, et al. Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations. Invest New Drugs 1998-1999; 16 (4):303-13.
49. Price A, Shi Q, Morris D, et al. Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Clin. Cancer Res.1999; 5(4):845-54.
50. Shalinsky DR, Brekken J, Zou H, et al. Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors:single agent and combination chemotherapy studies. Clin. Cancer Res.1999; 5(7):1905-17.
51. Ferrante K, Winograd B, Canetta R. Promising new developments in cancer chemotherapy. Cancer Chemother Pharmacol 1999; 43:61-8.
52. Rizvi NA, Humphrey JS, Ness EA, et al. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin. Cancer Res.2004; 10(6):1963-70.
53. Douillard JY, Peschel C, Shepherd F, et al. Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer.2004; 46 (3):361-8.
54. Selzer MG, Zhu B, Block NL, Lokeshwar BL. CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays the development of paraplegia in a rat model of prostate cancer. Arm. N Y Acad Sci.1999; 878:678-82.
55. Syed S, Takimoto C, Hidalgo M, et al. A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin. Cancer Res.2004; 10(19):6512-21.
56. Rudek MA, Figg WD, Dyer V, et al. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J. Clin. Oncol.2001; 19(2):584-92.
57. Fingleton B. CMT-3. CollaGenex. Curr. Opin. Investig Drugs 2003; 4:1460-7.
58. Stearns ME. Alendronate blocks TGF-betal stimulated collagen 1 degradation by human prostate PC-3 ML cells. Clin. Exp. Metastasis.1998; 16(4):332-9.
59. Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res.2001; 61(6):2602-8.
60. Mackie PS, Fisher JL, Zhou H, Choong PF. Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line. Br J. Cancer.2001; 84(7): 951-8.
61. Hamma-Kourbali Y, Di Benedetto M, Ledoux D, Oudar O, Leroux Y, Lecouvey M, Kraemer M. A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis. Biochem Biophys Res. Commun.2003; 310(3):816-23.
62. Eli Breuer, Claudio JS, Yiffat K, et al. Caramoylophosphonates, a new class of in vivo active matrix metalloproteinase inhibitor.1. alkyl-and cycloalkylcarbamoylphosphonic acids. J. Med. Chem.2004; 47:2826-2832.
63. Amnon H, Bashir Q, Julia F, et al. Caramoylophosphonate matrix metalloproteinase inhibitors 6:cis-2-aminocycloalkylcarbamoylphosphonic acid, a novel orally active antimetastic matrix metalloproteinase-2 selective inhibitor#Synthesis and pharmacodynamic and pharmacokinetic analysis. J. Med. Chem.2008; 51:1406-1414.
64. Lee HJ, Chung MC, Lee CH, et al. Gelastatins A and B, new inhibitors gelatinase from Westerdykella multispora F50733. Antibiot.1997; 50(4):357-9.
65. Kim EJ, Ko SY. Synthesis of arylidene-substituted gelastatin analogues and their screening for MMP-2 inhibitory activity. Bioorg. Med. Chem.2005; 13:4103-4112.
66. Zhang YM, Fan XD, Paul FJ, et al. 1-Hydroxy-2-pyridinone-based MMP inhibitors:syhthesis and biological evaluation for the treatment of ischemic stroke. Bioorganic & Medicinal Chemistry Letters.2008; 18(1):409-413.
67. Zhang L, Zhang J, Fang H, Wang Q, Xu WF. Design Synthesis and Preliminary Evaluation of New Cinnamoyl Pyrrolidine Derivatives as Potent Gelatinase inhibitors. Bioorg. Med. Chem. 2006; 14:8286-8294.
68. Li X, Li YL, Xu WF. Design, synthesis and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents. Bioorg. Med. Chem.2006; 14(5):1287-1293.
69. Li YL, Xu WF. Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors. Bioorg. Med. Chem.2004; 12:5171-5180.
70. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivertives as matrix metalloproteinase inhibitors. Bioorg. Med. Chem. 2008; 16(17):7932-8.
71. Qu X, Yuan Y, Xu W, et al. Caffeoyl pyrrolidine derivative LY52 inhibits tumor invasion and metastasis via suppression of matrix metalloproteinase activity. Anticancer Res.2006; 26(5A): 3573-8.
72. Yuan YX, Xu WF, Qu XJ, et al. Inhibitory effects of matrix metalloproteinase (MMP) inhibitor LY52 on expression of MMP-2 and MMP-9 and invasive ability of human ovarian carcinoma cell line SKOV3. Chin. J. Canc.2006; 25(6):663-70.
1. Feng YQ, John JL, Zhu LM, et al. Solution structure and backbone of the catalytic domain of matrix metalloproteinase-2 complexd with a hydroxamic acid inhibitor. Biochim. Biophys. Acta.2002; 1598:10-23.
2. Kramer RZ, Bella J, Mayville P, Brodsky B, Berman HM. Sequence dependent conformational variations of collagen triple-helical structure. Nature Structural Biology.1999; 6(5):454-457.
3.徐文方,等.药物设计学.人民卫生出版社,2007。
4. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr.Med. Chem.2008; 15(4):368-73.
1. Abraham DJ, Mokotoff M, Sheh L, Simmons JE. Design, synthesis, and testing of antisckling agents.2.1a,b proline derivatives designed for the donor site. J. Med. Chem.1983; 26: 549-554.
2. Hlavacek J, Bennettova B, Barth T, Tykva R. Synthesis, radiolabeling and biological activity of peptide oostatic hormone and its analogues. J. Pept. Res.1997; 50(3):15-158.
1. Baragi VM, Shaw BJ, Renkiewicz RR, et al. A versatile assay for gelatinase using succinylated gelatin. Anal. Biochem.2000; 286(1):267-273.
2. Baragi VM, Shaw BJ, Renkiewicz RR, et al. A versatile assay for gelatinases using succinylated gelatin. Matrix Biol,2000,19:267-273.
3. Drag M, Grembecka J, Pawelczak M, et al. a-Aminoalkylphosphonates as a tool in experimental optimisation of PI side chain shape of potential inhibitors in S1 pocket of leucineand neutral aminopeptidases. Eur. J. Med. Chem.2005; 40(8):764-771.
4. Raniera B, Arlette C, Jean-Mare G, et al. A novel Na-acetyl alanine amino-peptidase N from allomyces arbuscala. Biochemistry.2002; 84:309-319.
5. Teruki S, Kenji T, Kayoko H, et al. Aminopeptidase inhibitors Bestatin and actinoin inhibit cell proliferation of myeloma cells predominantly by intracellular interactivity. Cancer Letter. 2002; 182:113-119.
6. Zhang Y. J.; Feng, J. H.; Jia, Y. P.; Wang, X. J.; Zhang, L.; Liu, C. X.; Fang, H.; Xu. W. F. J. Med. Chem.2011,54,2823.
2.李凡、徐志凯主编,医学微生物学(第八版)人民卫生出版社，2013.
3. Kumarasamy, K.K., Toleman, M.A., Walsh, T.R., et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK:a molecular, biological, and epidemiological study. The Lancet infectious diseases,2010.10(9):597-602.
4. Hammerum, A.M., Toleman, M.A., Hansen, F., et al. Global spread of New Delhi metallo-β-lactamase 1. The Lancet infectious diseases,2010.10(12):829-830.
5.王媛媛，聂青和.肠出血性大肠杆菌O-104：H4型感染.中国实用内科杂志，2011,31(8)：616-618.
6.郑虎(主编),药物化学(第六版).人民卫生出版社，2008.
7.杨宝峰 主编 药理学 (第八版).人民卫生出版社，2013.
8. Clatworthy, A.E., E. Pierson, and D.T. Hung. Targeting virulence:a new paradigm for antimicrobial therapy. Nature chemical biology,2007.3(9):541-548.
9. Nikaido, H. and Vaara, M.. Molecular basis of bacterial outer membrane permeability. Microbiol Rev,1985,49(1):1-32.
10. Vaara, M.. Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria. Antimicrobial Agents and Chemotherapy, 1993,37(2):354-356.
11. Cock, H.D., Brandenburg, K., Wiese, A., et al. Non-lamellar structure and negative charges of lipopolysaccharides required for efficient folding of outer membrane protein PhoE of Escherichia coli. Journal of Biological Chemistry,1999.274(8):5114-5119.
12. Raetz, C. R. and Whitfield, C.. Lipopolysaccharide endotxins. Annual review of biochemistry, 2002,71(1):635-700.
13. Nikaido, H.. Molecular basis of bacterial outer membrane permeability revisited. Microbiology and Molecular Biology Reviews,2003,67(4):593-656.
14. Raetz, C. R.. Bacterial endotoxins:extraordinary lipids that activate eucaryotic signal transduction. Journal of Bacteriology,1993,175(18):5745-5743.
15. Vuorio, R. and Vaara M.. The lipid A biosynthesis mutation lpxA2 of Escherichia coli results in drastic antibiotic supersusceptibility. Antimicrobial Agents and Chemotherapy,1992,36(4): 826-829.
16. Anderson, M.S., C.E. Bulawa, and C. Raetz, The biosynthesis of gram-negative endotoxin. Formation of lipid A precursors from UDP-GlcNAc in extracts of Escherichia coli. Journal of Biological Chemistry,1985.260(29):15536-15541.
17. Anderson, M.S. and C. Raetz, Biosynthesis of lipid A precursors in Escherichia coli. A cytoplasmic acyltransferase that converts UDP-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)-N-acetyl glucosamine. Journal of Biological Chemistry, 1987.262(11):5159-5169.
18. Anderson, M. S., Bull, H. G., Galloway, S. M., et al. UDP-Nacetylglucosamine acyltransferase of Escherichia coli:The first step of endotoxin biosynthesis is thermodynamically unfavorable, J. Biol. Chem.,1993,268(26),19858-19865.
19. Wyckoflf, T.J.O., C.R.H. Raetz, and J.E. Jackman, Antibacterial and anti-inflammatory agents that target endotoxin. Trends in microbiology,1998.6(4):154-159.
20. White, R. J., Margolis, P. S., Trias, J., and Yuan, Z. Targeting metalloenzymes:A strategy that works. Curr. Opin. Pharmacol,2003,3(5):502-507.
21. Sorensen, P.G., Lutkenhaus, J., Young, K., et al. Regulation of UDP-3-O-[R-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase in Escherichia coli. The second enzymatic step of lipid a biosynthesis. J. Biol. Chem.,1996,271(42),25898-905.
22. Ogura, T., Inoue, K., Tatsuta, T, et al. Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli. Mol. Microbiol,1999,31(3):833-844.
23. Fiihrer, F., Langklotz, S. and Narberhaus, F. The C-terminal end of LpxC is required for degradation by the FtsH protease. Molecular Microbiology,2006,59(3):1025-1036.
24. Stover, C. K., Pham, X. Q., Erwin, A. L., et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature,2000,406(6799),959-964.
25. Blattner, F. R., Plunkett, G., Bloch, C. A., et al. The complete genome sequence of Escherichia coli K-12. Science,1997,277(5331):1453-1474.
26. Whittington, D. A., et al. Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis. PNAS,2003,100(14):8146-8150.
27. Coggins, B. E., Li, X. C., McClerren, A. L., et al. Structure of the LpxC deacetylase with a bound substrate-analog inhibitor. Nature Structural Biology,2003,10(8):645-651.
28. Coggins, B. E., McClerren, A. L., Jiang, L., et al. Refined solution structure of the LpxC-TU-514 complex and pKa analysis of an active site histidine:insights into the mechanism and inhibitor design. Biochemistry,2005,44(4):1114-1126.
29. Brab, A. W., Jiang, L., Raetz, C. R. et al. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090:Time-dependent inhibition and specificity in ligand binding. PNAS, 2007,104(47):18433-18438.
30. Mochalkin, I., Knafels, J. D. and Lightle, S.. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor. Protein Science,2008,17(3): 450-457.
31. Gennadios, H. and Christianson, D. W.. Binding of uridine 5'-diphosphate in the "basic patch" of the zinc deacetylase LpxC and implications for substrate binding. Biochemistry,2006, 45(51):15216-15223.
32. Brab, A. W. and Zou, P.. Mechanism and inhibition of LpxC:an essential zinc-dependent deacetylase of bacterial Lipid A synthesis. Curr. Pharm. Bio.,2008,9:9-15.
33. Buetow, L., Dawson, A. and Hunter W. N. The nucleotide-binding site of Aquifex aeolicus LpxC. Structural Biology And Crystallization Communications,2006,62(11):1082-1086.
34. Hernick, M., et al. UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase functions through a general acid-base catalyst pair mechanism. Journal of Biological Chemistry,2005,280(17):16969-16978.
35. McClerren, A. L., Zou, P., Guan, Z. Q., et al. Kinetic analysis of the zinc-dependent deacetylase in the Lipid A biosynthetic pathway. Biochemistry,2005,44(4):1106-1113.
36. Hernick, M. and Fierke, C. A.. Zinc hydrolases:the mechanisms of zinc-dependent deacetylases. Arch. Biochem. Biophys.,2005,433(1):71-84.
37. Gennadios, H., et al. Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase. Biochemistry,2006,45(26):7940-7948.
38. Zhang, J., Zhang, L., Li, X., Xu, W. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) Inhibitors:A New Class of Antibacterial Agents. Curr. Med. Chem., 2012,19,2038-2050.
39. Onishi, R. H., Pelak, B. A., Gerckens, L. S., et al.Antibacterial agents that inhibit Lipid A biosynthesis. Science,1996,274(5289):980-982.
40. Chen, M. H., Steiner, M. G., Laszlo, S. E., et al. Carbohydroxamido-oxazolidines: antibacterial agents that target lipid A biosynthesis. Bioorganic & medicinal chemistry Letters, 1999,9(3):313-318.
41. Jackman, J. E., Fierke, C. A., Tumey, L. N., et al. Antibacterial agents that target lipid A biosynthesis in Gram-negative bacteria. Journal of Biological Chemistry,2000,275(15): 11002-11009.
42. Mdluli, K. E., Witte, P. R., Kline, T., et al. Molecular validation of LpxC as an antibacterial drug target in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy,2006,50(6): 2178-2184.
43. Kline, T., Anderson, N. H., Harwood, E. A., et al. Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC. J. Med. Chem,2002,45(14):3112-3129.
44. Pirrung, M. C., Tumey, L. N., Raetz, C. R., et al. Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC):isoxazoline zinc amidase inhibitors bearing diverse metal binding groups. J. Med. Chem,2002,45(19):4359-4370.
45. Pirrung, M. C., Tumey, L. N., McClerren, A. L., et al. High-Throughput Catch-and-Release Synthesis of Oxazoline Hydroxamates. Structure-activity relationships in novel inhibitors of Escherichia coli LpxC:in vitro enzyme inhibition and antibacterial properties. J. Am. Chem. Soc,2003,125(6):1575-1586.
46. Clements, J. M., Coiqanard, F., Johnson, I., et al. Antibacterial activities and characterization of novel intibitors of LpxC. Antimicrob. Agents. Chemother.,2002,46(9):1793-1799.
47. Anderson, N. H., Bowman, J., Erwin, A., et al. Antibacterial agents. WO2004062601.2004.
48. McClerren, A. L., Endsly, S., Bowman, J. L., et al. A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of Lipid A biosynthesis with antibiotic activity comparable to Ciprofloxacin. Biochemistry,2005,44(50):16574-16583.
49. Barb, A. W., McClerren, A. L., Snehelatha K., et al. Inhibition of Lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry,2007, 46(12):3793-3802.
50. Cole, K. E., Gattis, S. G., Angell, H. D., et al. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090. Biochemistry,2011,50(2):258-265.
51. Lee, C. J., Liang, X. F., Chen X., et al. Species-specific and inhibitor-dependent conformations of LpxC:implications for antibiotic design. Chemistry & Biology,2010,18(1): 38-47.
52. Liang, X. F., Lee, C. J., Chen X., et al. Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem.,2011,19(2):852-860.
53. Liang, X. F., Lee, C. J., Zhao J. S., et al. Syntheses, structures and antibiotic activities of aryl-substituted LpxC inhibitors.J. Med. Chem.,2013,56(17):6954-66.
54. Brown, M. F., Reilly, U., Abramite, J. A., et al. Potent inhibitors of LpxC for the treatment of Gram-negative infections. J. Med. Chem.,2012,55(2):914-923.
55. Montgomery, J. I., Brown, M. F., Reilly, U., et al. Pyridone methylsulfone hydroxymate LpxC inhibitors for the treatment of serious Gram-negative infections. J. Med. Chem.,2012,55(4): 1662-1670.
56. Loppenberg, M., Miiller, H., Pulina, C., et al. Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors. Org. Biol. Chem.,2013,11(36):6056-70.
57. Szermerski, M., Melesina, J., Wichapong, K., et al. Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors. Bioorg. Med. Chem.,2014,22(3):1016-1028.
58. Mansoor, U. F., Reddy, P., Adulla, P., et al. Hydantoin derivatives useful as antibacterial agents. WO 2008/027466 Al.
59. Cuny, G. D.. A new class of UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections:PCT application WO 2008027466. Expert Opin. Then Patents,2009,19(6):893-899.
60. Brab, A. W., Leavy, T. M., Robins, L. I., et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry,2009,48(14):3068-3077.
61. Shin, H., Gennadios, H. A., Whittington, D. A., et al. Amphipathic benzoic acid derivatives: Synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC. Bioorg. Med. Chem.,2007,15(7):2617-2623.
1. Brab, A. W., Leavy, T. M., Robins, L. I., et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry,2009,48(14):3068-3077.
2.陈凯先,等。计算机辅助药物设计：原理、方法及应用。上海科学技术出版社,2000.
3.徐筱杰,等。计算机辅助药物分子设计。化学工业出版社,2004。
4.徐文方,等。药物设计学。人民卫生出版社,2007。
5. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr. Med. Chem.2008; 15(4):368-73.
6. Clements, J. M., Coiqanard, F., Johnson, I., et al. Antibacterial activities and characterization of novel intibitors of LpxC. Antimicrob. Agents. Chemother.,2002,46(9):1793-1799.
7. Ehrlieh, J., Bartz, Q. R., Smith, R.M., Joslyn, D.A., Burkholder, P.R. Chloromyeetin, a new antibiotic from a soil actinomycete. Scienee,1947,106,417.
8. Shatilo, V.A., Zaritskii, A.M., Kudrya. T.N., Shtepanek, A.S. Effect of 1-(p-nitrophenyl)-2-amino-1,3-propanediol and β-chloroethyl-phosphonic acid derivatives on growth of enterobacteria. Mikrobiologicheskii Zhurnal,1984,46(4):39-42.
9. Drainas, D., Petros, M., Coutsogeorgopoulos, C. Aminoaecyl analogs of chloramphenicol: examination of the kinetics of inhibition of peptide bond formation. J. Med. Chem.,1993, 36(23):3542-3545.
10. Liang, X. F., Lee, C. J., Chen X., et al.Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem.,2011,19(2):852-860.
1. Leadbeater, N.E., Macro, M.. Ligand-free Palladium catalysis of the suzuki reaction in water using microwave heating. Org. lett.,2002,4(17):2973-2976.
2. Shirakawa, E., Kitabata, T., Otsuka, H., Tsuchimoto, T.. A simple catalust system for the palladium-catalyzed coupling of aryl halides with terminal alkynes. Tetrahedron,2005,61, 9878-9885.
3. Percec, V., Rudick, J.G., Peterca, M., et al.Thermoreversible cis-cisoidal to cis-transoidal isomerization of helical dendronized polyphenylacetylenes. J. Am. Chem. Soc.,2005, 127(43):15257-64.
4. Mohamed Ahmed, M.S., Mori, A.. Sonogashira coupling with aqueous ammonia directed to the synthesis of azotolane derivatives. Tetrohedron,2004,60,9977-9982.
5. Vasilevsky, S.F., Klyatskaya, S.V., Elguero, J.. One-pot synthesis of monosubstituted aryl(hetaryl)acetylenes by direct introduction fo the CCH residue into arenes and hetarenes. Tetrohedron,2004,60,6685-6688.
6. Nicolaou, K. C., Zipkin R. E., Petasis, N. A.. The endiandric acid cascade. Electrocyclizations in organic synthesis.4. Biomimetic approach to endiandric acids A-G. Total synthesis and thermal studies. J. Am. Chem. Soc.,1982,104(20):5558-5560.
7. Jordis U, Sauter F, Siddiqi S M. Synthesis of (1S,4S)-2-thia-5-azabicyclo[2.2.1] heptane. Indian. J. Chem.,1989,28(B):294-6.
8. Catherine, J. L., Jerome, D., Anna, Q., et al. Preparation of pyrrolidine derivatives as oxytocin antagonists. WO 2004005249 Al 20040115.
9. Karoyan, P., Chassaing, G. Asymmetric synthesis of 3-alkyl substituted prolines by alkylation of a chiral sulfone. Tetrohedron Lett.,2002,43,1211-1223.
10. Bemardes, G.J.L., Chalker, J.M., Errey, J.C., Davis, B.G. Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces:versatile and switchable access to functionalized proteins. J. Am. Chem. Soc.,2008,130,5052-5053.
11. Hlavacek J, Bennettova B, Barth T, Tykva R. Synthesis, radiolabeling and biological activity of peptide oostatic hormone and its analogues. J. Pept. Res.,1997,50(3):15-158.
1. Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically: Approved Standard.{NCCLS document M7-A7),2006.
2. Jackman, J.E., Raetz, C.R., Fierke, C.A.. Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site. Biochemistry,2001,40(2):514-23.
3. Liang, X.F., Lee, C. J., Zhao, J.S., Toone, E.J., Zhou, P.. Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. J. Med. Chem.,2013,56(17):6954-66.
1. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation. Cell.1991; 64:327-335.
2. Stetler-Stevenson WG. Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol.1993; 9:541-573.
3. Sato H, Takino T, Okada Y. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 1994; 370:61-65.
4. Rundhaug, J. E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med.2005,9(2), 267-285.
5. Sounni NE, Janssen M, Foidart JM, Noel A. Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. Matrix Biol.2003; 22 (1):55-61.
6. Hideaki N, Woessner JF Jr. Matrix metalloproteinases. J. Biol. Chem.1999; 274(31): 21491-21494.
7. Neri M, Baaden M, Carnevale V, Anselmi C, Maritan A, Carloni P. Microseconds dynamics simulations of the outer-membrane protease T. Biophys 2008; 94 (1):71-78.
8. Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl Cancer Inst.1997; 89:1260-1270.
9. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. Engl. J. Med.1995; 333:1757-1763.
10. Mira E, Manes S, Lacalle RA, et al. Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology 1999; 140:1657-1664.
11. Martin DC, Fowlies JL, Babic B, et al. Insulin-like growth factor Ⅱ signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J. Cell Biol.1999; 146:881-892.
12. Manes S, Mira E, Barbacid MM, et al. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J. Biol. Chem.1997; 272:25706-25712.
13. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res.1998; 58:1135-1139.
14. Angelo V, Domenico R, Marco P, et al. Blood.1999; 93(9):3064-3073.
15. Ray JM; Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J.1994; 7 (11):2062-72.
16. O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell.1994; 79 (2): 315-28.
17. Giannelli G; Falk-Marzillier J; Schiraldi O; Stetler-Stevenson WG; Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science.1997; 277(5323): 225-8.
18. Kontogiorgis CA, Papaioannou P, Hadjipavlou L DJ. Matrix metalloproteinase inhibitors:a review on pharmacophore mapping and (Q)SARs results. Curr. Med. Chem.2005; 12(3): 339-55.
19. Kugler A. Matrix metalloproteinases and their inhibitors. Anticancer Res.1999; 19(2C): 1589-92.
20. MacDougall JR; Bani MR; Lin Y; Muschel RJ; Kerbel RS.'Proteolytic switching':opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression. Br. J. Cancer 1999; 80(3-4): 504-12.
21. Nagase H; Woessner JF Jr. Matrix metalloproteinases. J. Biol. Chem.1999; 274 (31): 21491-4.
22. Strongin AY; Collier I; Bannikov G; Marmer BL; Grant GA; Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem.1995; 270 (10):5331-8.
23. Caterina J, Shi J, Krakora S, et al. Isolation, characterization, and chromosomal location of the mouse enamelysin gene. Genomics 1999; 62(2):308-11.
24. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res.1998; 58(6):1135-9.
25. Suemitsu R, Yoshino I, Tomiyasu M, et al. Serum tissue inhibitors of metalloproteinase-1 and-2 in patients with non-small cell lung cancer. Surg. Today 2004; 34 (11):896-901.
26. Nagel H, Laskawi R, Wahlers A, Hemmerlein B. Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1,-2, and-3 in benign and malignant tumours of the salivary gland. Histopathology 2004; 44 (3):222-31.
27. Peterson JT. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev 2004; 9(1):63-79.
28. Annabi B, Lachambre M P, Bousquet-Gagnon N, Page M,Gingras D, Beliveau R. Green tea polyphenol (-)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MTl-MMP-driven migration in glioblastoma cells. Biochim. Biophys. Acta.2002; 1542:209-220.
29. Garbisa S, Sartor L, Biggin S, Salvato B, Benelli R, Albini A.Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate. Cancer.2001; 91:822-832.
30. Oneda H, Shiihara M, Inouye K. Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin). Biochem.2003; 133 (5):571-576.
31. Mannello F. Natural bio-drug as matrix metalloproteinase inhibitors:new perspectives on the horizon? Recent Patents on Anti-Cancer Drug Discovery.2006; 1:91-103.
32. Park WH, Kim SH, Kim CH. A new matrix metalloproteinase-9 inhibitor 3,4-dihydroxycinamic acid(caffeic acid) from methanol extract of Eunonymus alatus: isolation and structure determination. Toxicology.2005; 207(3):383-90.
33. Sartor L, Pezzato E, Dell'Aica Ⅰ, Caniato R, Biggin S, Garbisa S.Inhibition of matrix-proteases by polyphenols:chemical insights for anti-inflammatory and anti-invasion drug design. Biochemical Pharmacology.2002; 64:22-237.
34. Puerta, DT, Lewis JA, Cohen SM. New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups. J. Am. Chem. Soc.2004; 126:8388-8389.
35. Puerta DT, Griffin MO, Cohen, SM, et al. Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors:potency, toxicity, and reactivity. J. Biol. Inorg. Chem.2006; 11:131-138.
36. Ikezoe T, Chen SS, Tong XJ, et al. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int. J. Oncol.2003; 23(4):1187-1193.
37.吴婕,袁守军,杨德宣,田增月。冬凌草甲素抑制BGC823细胞的生长及MMP-2, MMP-9的表达。解放军药学学报2007；23(5)：344-347.
38. Breuer E, Frant J, Reich R. Recent non-hydroxamate matrix metalloproteinase inhibitors. Expert Opin. Then Pat.2005; 15(3):253-269.
39. Fujita M, Nakao Y, Matsunaga S, et al. Ageladine A:an antiangiongenic matrix metalloproteinase inhibitor from the marine sponge agelas nakamurai. J. Am. Chem. Soc.2003; 125(51):15700-15701.
40. Giavazzi R, Garofalo A, Ferri C, et al. A synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts. Clin. Cancer Res.1998; 4(4):985-92.
41. Prontera C, Mariani B, Rossi C, Poggi A, Rotilio D. Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. Int. J. Cancer.1999; 81 (5):761-6.
42. Macaulay VM, O'Byrne KJ, Saunders MP, et al. Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin. Cancer Res.1999; 5(3):513-20.
43. Wojtowicz-Praga S, Torri J, Johnson M, et al. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J. Clin. Oncol.1998; 16(6):2150-6.
44. Primrose JN, Bleiberg H, Daniel F, et al. Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen. Br J. Cancer 1999; 79(3-4):509-14.
45. Steward WP. Marimastat (BB2516):current status of development. Cancer Chemother Pharmacol.1999; 43:56-60.
46. Peterson JT. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev.2004; 9(1):63-79.
47. Shalinsky DR, Brekken J, Zou H, et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann.N Y Acad Sci.1999; 878:236-70.
48. Shalinsky DR, Brekken J, Zou H, et al. Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations. Invest New Drugs 1998-1999; 16 (4):303-13.
49. Price A, Shi Q, Morris D, et al. Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Clin. Cancer Res.1999; 5(4):845-54.
50. Shalinsky DR, Brekken J, Zou H, et al. Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors:single agent and combination chemotherapy studies. Clin. Cancer Res.1999; 5(7):1905-17.
51. Ferrante K, Winograd B, Canetta R. Promising new developments in cancer chemotherapy. Cancer Chemother Pharmacol 1999; 43:61-8.
52. Rizvi NA, Humphrey JS, Ness EA, et al. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin. Cancer Res.2004; 10(6):1963-70.
53. Douillard JY, Peschel C, Shepherd F, et al. Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer.2004; 46 (3):361-8.
54. Selzer MG, Zhu B, Block NL, Lokeshwar BL. CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays the development of paraplegia in a rat model of prostate cancer. Arm. N Y Acad Sci.1999; 878:678-82.
55. Syed S, Takimoto C, Hidalgo M, et al. A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin. Cancer Res.2004; 10(19):6512-21.
56. Rudek MA, Figg WD, Dyer V, et al. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J. Clin. Oncol.2001; 19(2):584-92.
57. Fingleton B. CMT-3. CollaGenex. Curr. Opin. Investig Drugs 2003; 4:1460-7.
58. Stearns ME. Alendronate blocks TGF-betal stimulated collagen 1 degradation by human prostate PC-3 ML cells. Clin. Exp. Metastasis.1998; 16(4):332-9.
59. Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res.2001; 61(6):2602-8.
60. Mackie PS, Fisher JL, Zhou H, Choong PF. Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line. Br J. Cancer.2001; 84(7): 951-8.
61. Hamma-Kourbali Y, Di Benedetto M, Ledoux D, Oudar O, Leroux Y, Lecouvey M, Kraemer M. A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis. Biochem Biophys Res. Commun.2003; 310(3):816-23.
62. Eli Breuer, Claudio JS, Yiffat K, et al. Caramoylophosphonates, a new class of in vivo active matrix metalloproteinase inhibitor.1. alkyl-and cycloalkylcarbamoylphosphonic acids. J. Med. Chem.2004; 47:2826-2832.
63. Amnon H, Bashir Q, Julia F, et al. Caramoylophosphonate matrix metalloproteinase inhibitors 6:cis-2-aminocycloalkylcarbamoylphosphonic acid, a novel orally active antimetastic matrix metalloproteinase-2 selective inhibitor#Synthesis and pharmacodynamic and pharmacokinetic analysis. J. Med. Chem.2008; 51:1406-1414.
64. Lee HJ, Chung MC, Lee CH, et al. Gelastatins A and B, new inhibitors gelatinase from Westerdykella multispora F50733. Antibiot.1997; 50(4):357-9.
65. Kim EJ, Ko SY. Synthesis of arylidene-substituted gelastatin analogues and their screening for MMP-2 inhibitory activity. Bioorg. Med. Chem.2005; 13:4103-4112.
66. Zhang YM, Fan XD, Paul FJ, et al. 1-Hydroxy-2-pyridinone-based MMP inhibitors:syhthesis and biological evaluation for the treatment of ischemic stroke. Bioorganic & Medicinal Chemistry Letters.2008; 18(1):409-413.
67. Zhang L, Zhang J, Fang H, Wang Q, Xu WF. Design Synthesis and Preliminary Evaluation of New Cinnamoyl Pyrrolidine Derivatives as Potent Gelatinase inhibitors. Bioorg. Med. Chem. 2006; 14:8286-8294.
68. Li X, Li YL, Xu WF. Design, synthesis and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents. Bioorg. Med. Chem.2006; 14(5):1287-1293.
69. Li YL, Xu WF. Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors. Bioorg. Med. Chem.2004; 12:5171-5180.
70. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivertives as matrix metalloproteinase inhibitors. Bioorg. Med. Chem. 2008; 16(17):7932-8.
71. Qu X, Yuan Y, Xu W, et al. Caffeoyl pyrrolidine derivative LY52 inhibits tumor invasion and metastasis via suppression of matrix metalloproteinase activity. Anticancer Res.2006; 26(5A): 3573-8.
72. Yuan YX, Xu WF, Qu XJ, et al. Inhibitory effects of matrix metalloproteinase (MMP) inhibitor LY52 on expression of MMP-2 and MMP-9 and invasive ability of human ovarian carcinoma cell line SKOV3. Chin. J. Canc.2006; 25(6):663-70.
1. Feng YQ, John JL, Zhu LM, et al. Solution structure and backbone of the catalytic domain of matrix metalloproteinase-2 complexd with a hydroxamic acid inhibitor. Biochim. Biophys. Acta.2002; 1598:10-23.
2. Kramer RZ, Bella J, Mayville P, Brodsky B, Berman HM. Sequence dependent conformational variations of collagen triple-helical structure. Nature Structural Biology.1999; 6(5):454-457.
3.徐文方,等.药物设计学.人民卫生出版社,2007。
4. Cheng XC, Wang Q, Fang H, Tang W, Xu WF. Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr.Med. Chem.2008; 15(4):368-73.
1. Abraham DJ, Mokotoff M, Sheh L, Simmons JE. Design, synthesis, and testing of antisckling agents.2.1a,b proline derivatives designed for the donor site. J. Med. Chem.1983; 26: 549-554.
2. Hlavacek J, Bennettova B, Barth T, Tykva R. Synthesis, radiolabeling and biological activity of peptide oostatic hormone and its analogues. J. Pept. Res.1997; 50(3):15-158.
1. Baragi VM, Shaw BJ, Renkiewicz RR, et al. A versatile assay for gelatinase using succinylated gelatin. Anal. Biochem.2000; 286(1):267-273.
2. Baragi VM, Shaw BJ, Renkiewicz RR, et al. A versatile assay for gelatinases using succinylated gelatin. Matrix Biol,2000,19:267-273.
3. Drag M, Grembecka J, Pawelczak M, et al. a-Aminoalkylphosphonates as a tool in experimental optimisation of PI side chain shape of potential inhibitors in S1 pocket of leucineand neutral aminopeptidases. Eur. J. Med. Chem.2005; 40(8):764-771.
4. Raniera B, Arlette C, Jean-Mare G, et al. A novel Na-acetyl alanine amino-peptidase N from allomyces arbuscala. Biochemistry.2002; 84:309-319.
5. Teruki S, Kenji T, Kayoko H, et al. Aminopeptidase inhibitors Bestatin and actinoin inhibit cell proliferation of myeloma cells predominantly by intracellular interactivity. Cancer Letter. 2002; 182:113-119.
6. Zhang Y. J.; Feng, J. H.; Jia, Y. P.; Wang, X. J.; Zhang, L.; Liu, C. X.; Fang, H.; Xu. W. F. J. Med. Chem.2011,54,2823.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |