Novel nitric oxide-releasing derivatives of pyranocarbazole as antitumor agents: Design, synthesis, biological evaluation, and nitric oxide release studies

In this study, a series of novel furoxan-based nitric oxide (NO) releasing derivatives of pyranocarbazole alkaloids were designed, synthesized, and biologically evaluated against human cancer cell lines. The derivatives showed considerable antiproliferative activities (IC50 = 0.05–7.55 μM) and most compounds showed higher activity in MDA-MB-231 than H460 and HeLa. Especially, the most active derivative 7a (IC50 = 0.05 μM) against MDA-MB-231 was about 60 times stronger than lead compound, as well as equivalent to positive control taxol, and produced high levels of NO in MDA-MB-231. Furthermore, 7a could significantly inhibit the growth of MDA-MB-231 tumors in vivo with low toxicity and the PI3K/Akt signaling pathway. These results indicated that compound 7a could be a promising lead for further studies. [Display omitted] •12 new pyranocarbazole/nitric oxide (NO) hybrids were designed and synthesized.•7a exhibited the most potent antiproliferative activity (IC50 = 0.05 μM) against MDA-MB-231.•7a produced the highest levels of NO intracellularly.•7a could arrest cell cycle at G0/G1 phase, induce cell apoptosis by inhibiting the PI3K/Akt signaling pathway.•7a inhibit the growth of EMT6 and MDA-MB-231 in vivo.