BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors.
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 (94.45Å2), 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 2.5-10.0μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC50=39.5±2.9nM to as low as 0.056±0.03nM). 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.
Compound Profiling Laboratory, Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
Judit
J
Müller
Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
Ana
A
Martins
Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
József
J
Csábi
Department of Pharmaceutical Technology, University of Debrecen, Nagyerdei St. 98, Debrecen H-4010, Hungary.
Ferenc
F
Fenyvesi
Compound Profiling Laboratory, Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
Árpád
Á
Könczöl
Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary; Interdisciplinary Centre for Natural Products, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary. Electronic address: hunyadi.a@pharm.u-szeged.hu.
Attila
A
Hunyadi
Compound Profiling Laboratory, Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary. Electronic address: gy.balogh@richter.hu.
György T
GT
Balogh
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D055598:Chemical Phenomena; D016503:Drug Delivery Systems / Q000379:methods; D026461:Ecdysteroids / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008567:Membranes, Artificial
D000970:Antineoplastic Agents; D026461:Ecdysteroids; D008567:Membranes, Artificial
Adjuvant; Cancer; Chemo-sensitization; Ecdysteroid; Lead selection; PAMPA-BBB; Physicochemical profiling