Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms221910695
Keywords
pentacyclic triterpenes; Claisen-Schmidt reaction; anticancer activity; apoptosis; antiangiogenic; molecular docking
Funding
- Russian Foundation for Basic Research [19-33-60083]
- Romanian UEFISCDI national grant [PN-III-P1-1.1-PD-2019-1078]
- Internal grant at Victor Babes University of Medicine and Pharmacy [1EXP/1233/30.01.2020]
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In this study, modified lupane and ursane derivatives showed high activity in inhibiting cancer cell proliferation by inducing apoptotic cell death. The compounds 6 and 7 exhibited high inhibitory activity against the antiapoptotic protein Bcl-XL, suggesting a potential mechanism for inducing apoptotic cell death.
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 GI(50) values ranging from 0.03 mu M to 5.9 mu M (compound 6) and 0.18-1.53 mu M (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.
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