Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 11, Issue -, Pages -Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S140164
Keywords
isatins; hybridization approach; antiproliferative; apoptosis
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Funding
- National Plan for Science, Technology and Innovation (MAARIFAH)
- King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia [11-MED1924-02]
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In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline (6a-f and 7a-e)/phthalazine (8a-f)/quinoxaline (9a-f) hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids 8b-d emerged as the most active antiproliferative congener in this study. Compound 8c induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 mu M against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid 8c was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry.
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