Back to Search
Start Over
Design and Synthesis of C-8 spiro-isoxazoline analogues of 14-Deoxy-11,12-didehydroandrographolide (14-DDA) for dual targeting of CDK4 and BCL2 mediated anticancer activity.
- Source :
-
Journal of Molecular Structure . Feb2024:Part 2, Vol. 1298, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- • C-8 spiro-isoxazoline derivatives of andrographolide were synthesised. • 4k displayed most potent cytotoxicity (IC 50 =3 μM) in breast cancer cells (MCF-7). • 4k increased the production of cellular and mitochondrial ROS, decreased the MMP, and inhibited the colony formation. • 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. 14-Deoxy-11,12-didehydroandrographolide (14-DDA, 3), a secondary metabolite found in Andrographis paniculata nees , has been synthetically modified into a new series of C-8 spiro-isoxazoline derivatives. Andrographolide and its derivatives were well reported for the anticancer activity so herein we have synthesised C-8 spiro-isoxazoline derivatives (4a-l) and screened for in vitro studies against four human cancer cell lines: breast (MCF-7), lung (A549), pancreatic (MiaPaCa-2), and prostate (PC-3). Most of the synthesized compounds exhibited better anti-cancer activities than the parent natural products andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (3) for different human cancer lines. Among all compounds, compound 4k displayed most potent cytotoxicity (IC 50 =3 μM) in breast cancer cells (MCF-7). Further, mechanistic studies revealed that compound 4k affected the nuclear morphology of MCF-7 cells, increased the production of cellular and mitochondrial ROS, decreased the mitochondrial membrane potential (MMP), and inhibited the colony formation. The compound 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. The expression of Cdk-4 was also downregulated by 4k. The overall findings of this study indicate that the compound 4k exhibited significant anticancer activity with reduced toxicity in-vitro and might thus be a promising anti-cancer lead candidate. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222860
- Volume :
- 1298
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular Structure
- Publication Type :
- Academic Journal
- Accession number :
- 173943730
- Full Text :
- https://doi.org/10.1016/j.molstruc.2023.137072