RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Sulfonamidas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Femenino , Semivida , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Endogámicas F344 , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante Heterólogo , Venas Umbilicales/citología , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
The anti-proliferative activity of acylated heterocyclic sulfonamides is described in Vascular Endothelial Growth Factor-dependent Human Umbilical Vascular Endothelial Cells (VEGF-HUVEC) and in HCT116 tumor cells in a soft agar diffusion assay.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Línea Celular Tumoral , Células Cultivadas , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Relación Estructura-Actividad , Venas Umbilicales/citología , Factor A de Crecimiento Endotelial VascularRESUMEN
The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03 = 2.4 log kill (LK); Panc-02 = 2.9-4.1 LK; Squamous Lung LC-12 = 2.1 LK; Colon-26 = 2.2 LK; AML1498 = 2.7 LK; Human Sm Cell Lung DMS-273 = 6.3 LK; Human Squamous Lung 165 = 3.7 LK; Human Ovarian BG-1 = 3.7 LK; Human Colon CX-1 (H29) = 1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor) = 2.3 LK; Human CNS-gliosarcoma-SF295 = 3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C = 0.6 LK; Mammary Adenocarcinoma-17 = no kill; Colon Adenocarcinoma-11 = no kill; L1210 leukemia = 1.3 LK; Human Prostate PC-3 = 0.5 LK; Human Adenosquamous Lung H125 = no kill; and Human Breast Adenocarcinoma MX-1 = 0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the "hit and miss" efficacy has not been determined.