BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors

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• 作者：Judit Mü ; ller^a ; Ana Martins^b ; ¹ ; Jó ; zsef Csá ; bi^c ; Ferenc Fenyvesi^d ; Á ; rpá ; d K&ouml ; ncz&ouml ; l^a ; Attila Hunyadi^c ; ^e ; ^{hunyadi.a@pharm.u-szeged.hu} ; Gy&ouml ; rgy T. Balogh^a ; ^{gy.balogh@richter.hu}
• 关键词：PAMPA-BBB ; Physicochemical profiling ; Lead selection ; Ecdysteroid ; Cancer ; Adjuvant ; Chemo-sensitization
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：571-577
• 全文大小：709 K
• 卷排序：96

文摘

The anticancer potential of ecdysteroids, especially their chemo-sensitizing activity has recently gained a substantial scientific interest. A comprehensive physicochemical profiling was performed for a set of natural or semi-synthetic ecdysteroids (N = 37) to identify a lead compound against central nervous system (CNS) tumors. Calculated properties, such as lipophilicity (clogP), topological polar surface area (TPSA), brain-to-plasma ratio (clogBB) along with the measured blood-brain barrier specific in vitro permeability (logPe) were evaluated in parallel. Compounds with the highest CNS-availability predicted (clogBB > 0.0 and logPe > − 6.0) showed moderate to high lipophilicity (clogP = 3.89 − 5.25), relatively low TPSA (94.45 Å2), and shared a common apolar 2,3- and 20,22-diacetonide motif (25, 30–33). These ecdysteroids were selected for testing their capacity to sensitize SH-SY5Y neuroblastoma cells to vincristine. All of the five tested compounds exerted a remarkably strong, dose dependent chemo-sensitizing activity: at 2.5–10.0 μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC50 = 39.5 ± 2.9 nM to as low as 0.056 ± 0.03 nM). Moreover, analysis of the combination index (CI) revealed outstanding synergism between ecdysteroids and vincristine (CI50 = 0.072 − 0.444). Thus, based on drug-likeness, physchem character and in vitro CNS activity, compound 25 was proposed as a lead for further in vivo studies.