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

Müller, Judit and Martins, Ana and Csábi, József and Fenyvesi, Ferenc and Könczöl, Árpád and Hunyadi, Attila and Balogh, György Tibor (2017) BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 96. pp. 571-577. ISSN 0928-0987

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Abstract

Abstract 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.

Item Type: Article
Uncontrolled Keywords: Chemo-sensitization; adjuvant; CANCER; ecdysteroid; Lead selection; physicochemical profiling; PAMPA-BBB
Subjects: R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 24 Jan 2018 10:41
Last Modified: 24 Jan 2018 10:41
URI: http://real.mtak.hu/id/eprint/73271

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