Flavone-based dual PARP-Tubulin inhibitor manifesting efficacy against endometrial cancer
Sachin Sharma, Kavya Chandra, Aliva Naik, Anamika Sharma, Ram Sharma, Amandeep Thakur, Ajmer Singh Grewal, Ashwani K. Dhingra, Arnab Banerjee, Jing‐Ping Liou, Santosh Kumar Guru, Kunal Nepali
Abstract
Structural tailoring of the flavone framework (position 7) via organopalladium-catalyzed C–C bond formation was attempted in this study. The impact of substituents with varied electronic effects (phenyl ring, position 2 of the benzopyran scaffold) on the antitumor properties was also assessed. Resultantly, the efforts yielded a furyl arm bearing benzopyran possessing a 4-fluoro phenyl ring (position 2) (14) that manifested a magnificent antitumor profile against the Ishikawa cell lines mediated through dual inhibition of PARP and tubulin [(IC50 (PARP1) = 74 nM, IC50 (PARP2) = 109 nM) and tubulin (IC50 = 1.4 µM)]. Further investigations confirmed the ability of 14 to induce apoptosis as well as autophagy and cause cell cycle arrest at the G2/M phase. Overall, the outcome of the study culminated in a tractable dual PARP-tubulin inhibitor endowed with an impressive activity profile against endometrial cancer.