Indole phytoalexins-derived bis-indoles: Design, synthesis and in vitro antiproliferative evaluation

Natural indole phytoalexins isolated from Brassicaceae plants have been identified as promising anticancer leads. Herein, we designed and synthesized six novel bis-indole series as indole phytoalexins analogues. Our design is based on replacing the SCH3 group in the natural leads by the peripheral indole ring. The key first series - bis indole thioureas, prepared from starting [1-(tert-butoxycarbonyl)indol-3-yl]methyl isothiocyanate and 1substituted (indol-3-yl)methylamine derivatives, were further transformed by oxidative spirocyclization with chromium oxide, bromospirocyclization protocol or methyl bromoacetate. The in vitro antiproliferation/cytotoxicity assays against human cancer cell lines demonstrated the bis-indole spirocompounds cis-28b and cis-31b were the most active compounds exhibiting a similar extent of effects against HeLa and HCT116 cells (a range of IC50 values between 7.4 and 10.8 & mu;M). At the same time, their activities were higher or comparable to cisplatin. Furthermore, compounds cis-28b and cis-31b displayed good selectivity indexes (SIs) spanning in the range 9.3-13.5. Collective, these results show that reported bis-indoles are promising candidate for cervix and colon cancer treatment and suitable for further investigations.