3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis

Author:

Kazakova OxanaORCID,Șoica Codruța,Babaev MaratORCID,Petrova AnastasiyaORCID,Khusnutdinova ElmiraORCID,Poptsov AlexanderORCID,Macașoi Ioana,Drăghici GeorgeORCID,Avram ȘtefanaORCID,Vlaia Lavinia,Mioc Alexandra,Mioc Marius,Dehelean Cristina,Voicu Adrian

Abstract

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18–1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4′,6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.

Funder

Russian Foundation for Basic Research

Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii

“Victor Babes” University of Medicine and Pharmacy

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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