Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma.

摘要: Abstract Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget Synthesized initially evaluated their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 20a exhibited more potent activity against HepG2 cells (IC50 = 4.69 12.5 µM, respectively) than reference Erlotinib (IC50 = 25 µM). Interestingly, NO-CIEA exerted also high Erlotinib-resistant cell line (HepG2-R) (IC50 = 8.21 µM) giving insight about its importance in resistance therapy. Intracellular measurements NO revealed that showed significant increase production tumor after 1 h incubation comparable to prodrug JS-K. Flow cytometric analysis both mainly arrested G0/G1 phase. Also, In-Cell Based ELISA screening resulted potential inhibitory towards EGFR MAPK (25% 29% inhibition compared untreated control cells, respectively). This data suggests binding ability ERK be correlated along with docking cellular studies. treatment HepG2-R reduction MRP2 expression dose dependent manner providing impact on chemotherapeutic resistance. Overall, current study provides new approach discovery agent HCC.