Acyl Sulfonamide Anti-Proliferatives:  Benzene Substituent Structure−Activity Relationships for a Novel Class of Antitumor Agents

Abstract

Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.

Candidate Biomarkers of Response to an Experimental Cancer Drug Identified through a Large-scale RNA Interference Genetic Screen

“…It was shown previously that acyl sulfonamides have prominent antiproliferative effects in cancer cell lines (1)(2)(3)(4). We have synthesized a novel acyl sulfonamide, R3200 (Fig.…”

“…The identification and characterization of new compounds that potentially specifically kill cancer cells is therefore of major interest. Recently, a new class of compounds was shown to be effective in inhibiting the growth of cancer cells in vitro and in vivo: the acyl sulfonamides (1)(2)(3)(4). However, the efficacy of these acyl sulfonamides varies greatly, depending on the cell models used.…”

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

“…Sulfonamides are important compounds in medicinal chemistry [30,31,32,33,34,35,36,37,38,39,40], and, in particular, N-acylated derivatives have revealed interesting antitumor activities in combination with attractive pharmacokinetics [41,42]. As surrogates for sulfonamides, the corresponding sulfonimidamides have lately been promoted (Fig.…”

Tasisulam Sodium, an Antitumor Agent That Inhibits Mitotic Progression and Induces Vascular Normalization

“…A requirement of the screen was to identify compounds that had approximately a 100-fold margin of activity between cancerous and nontransformed normal cells. In vitro, tasisulam is a potent antiproliferative compound (free drug EC 50 typically in the low mmol/L range) and displays preferential cancer cell death relative to normal, untransformed human cell lines (10,11). Furthermore, NCI COMPARE analysis indicates that tasisulam possesses a unique mechanism of action relative to other agents (10,12).…”

“…In vitro, tasisulam is a potent antiproliferative compound (free drug EC 50 typically in the low mmol/L range) and displays preferential cancer cell death relative to normal, untransformed human cell lines (10,11). Furthermore, NCI COMPARE analysis indicates that tasisulam possesses a unique mechanism of action relative to other agents (10,12). In humans, tasisulam has shown activity in several different tumor subtypes, and clinical studies are ongoing or completed in soft tissue sarcoma, ovarian cancer, acute myeloblastic leukemia, metastatic breast cancer, non-small cell lung cancer, and renal cancers (13)(14)(15).…”