Minilibrary of 6-bromo derivatives of indole phytoalexins: Synthesis, anticancer profile and structure-activity relationship (SAR) study

In this study, we synthesized a minilibrary of twenty-two derivatives of indole phytoalexins containing bromine atom at the position 6 of the indole ring. A short efficient synthesis of novel 6-bromo-1-Boc-brassinin and its amino analogues was achieved, starting from 6-bromo-1H-indole-3-carboxaldehyde in a four-step and a five-step protocol, respectively. In the preparation of the spirocyclic products, electrophilic - nucleophilic 3,2-difunctionalization of the indole core was chosen using bromospirocyclization of 6-bromo-1-Boc-brassinin or thiourea derivatives and subsequent reaction with nucleophiles (methanol or the appropriate aniline). A TFA-promoted cascade reactions of spirocyclic products resulted in the formation of 7-bromocyclobrassinin and its 2-amino analogues. The in vitro antiproliferative activities of prepared compounds were evaluated against a panel of human cancer cell lines and non-malignant cells using the MTT assay and some structure–activity relationships were observed. Results of antiproliferative screening indicated that 3,4-dichlorophenylamino analogue of 6-bromo-1-Boc-brassinin was the most potent (IC₅₀ = 7.1 μM against HCT116 cells, IC₅₀ = 8.8 μM against A549 cells, IC₅₀ = 7.5 μM against Jurkat cells). This compound showed higher antiproliferative activity compared to cisplatin. However, this compound also significantly decreased non-cancer cell proliferation (MCF-10, IC₅₀ = 7.7 μM and Cos-7, IC₅₀ = 12.6 μM). Compounds with 4-(trifluoromethyl)phenylamino and 3,4-dichlorophenylamino moiety tend to have higher IC₅₀ values across multiple cell lines compared to parent compounds with the SCH₃ group. The SAR study demonstrated that the incorporation of bromine at the position 6 of indole led to a decrease or loss of activity in most cases.