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

• Published in: Tetrahedron Vol. 143; pp. 133573 - 133587
• Main Authors: Budovska, Mariana, Michalkova, Radka, Mojzis, Jan
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 21.08.2023; Elsevier
• Subjects: Antiproliferative/cytotoxic activity; Bis-indoles; Chemistry; Chemistry, Organic; Cyclization reactions; Indole phytoalexins; Physical Sciences; Science & Technology; Cyclization reactions; Bis-indoles; Antiproliferative/cytotoxic activity; Indole phytoalexins; Antiproliferative; APOPTOSIS; ANALOGS; BRASSININ; SPIROBRASSININ; ANTICANCER ACTIVITY; INHIBITION; cytotoxic activity; 1-METHOXYSPIROBRASSINOL METHYL-ETHER; DERIVATIVES
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2023.133573

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 1-substituted (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 μM). 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. [Display omitted] •Syntheses of novel bis-indole analogues of natural indole phytoalexins were accomplished.•The used strategy relied on oxidative cyclization, bromospirocyclization and methyl bromoacetate-mediated cyclization.•Bis-indole spirocompounds were active against HeLa, HCT116 cells and at the same time had a good selectivity and safety profile.