Flavone-based dual PARP-Tubulin inhibitor manifesting efficacy against endometrial cancer

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.

GRAPHICAL ABSTRACT

Keywords:

• Flavone
• benzopyran
• PARP
• tubulin
• inhibitor
• endometrial cancer

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

Kunal Nepali is supported by the Ministry of Science and Technology, Taiwan, and the National Science and Technology Council (grant no. MOST-111–2320-B-038 –047 - and NSTC-112–2320-B-038–030-). Jingping Liou is supported by the Ministry of Science and Technology, Taiwan (Grant no. MOST111-2113-M038-004). Santosh Kumar Guru is supported by SERB: SRG/2020/002013. Arnab Banerjee would like to thank DBT, GOI, for the financial assistance (ongoing grant: BT/INF/22/SP42543/2021) and Dr. Geetanjali Sachdeva and Dr. Uddhav Chaudhari of National Institute From Research in Reproductive and Child Health (NIRRCH), Mumbai for gifting the ISHIKAWA cell lines.