Synthesis and structure-activity relationship of mono-indole-, bis-indole-, and tris-indole-based sulfonamides as potential anticancer agents.

A series of arylsulfonyl mono-indoles (10-15), bis-indoles (16-27), and tris-indoles (28-32) have been synthesized and evaluated for their cytotoxicity toward four human cancer cell lines including HuCCA-1 (cholangiocarcinoma), HepG2 (hepatocellular carcinoma), A-549 (lung carcinoma), and MOLT-3 (lymphoblastic leukemia). Most of the synthesized indoles displayed cytotoxicity against the MOLT-3 cell line except for analogs 16, 17, and 32. Significantly, the [Formula: see text]-sulfonylphenolic bis-indole series (18-27) and the [Formula: see text]-chlorobenzenesulfonyl tris-indole (30) showed higher antiproliferative activity against HepG2 cell than the reference drug, etoposide. Promisingly, the [Formula: see text]-chlorobenzenesulfonyl bis-indole (20) and tris-indole (30) provided 3-fold and 2-fold stronger activity, respectively, against HepG2 cell than etoposide. Moreover, the phenolic bis-indole (20) was also shown to be the most potent cytotoxic agent against HuCCA-1 and A-549 cell lines with [Formula: see text] values of 7.75 and [Formula: see text], respectively. The tris-indole analogs 28, 29, and 31 also exhibited selectivity against MOLT-3 cell. The findings disclosed that [Formula: see text]-arylsulfonyl bis-indoles-bearing phenolic groups are potentially interesting lead pharmacophores of anticancer agents that should be further investigated in more detail.