Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.
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.
Lobb
Karen L
KL
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Lobb_Karen@Lilly.com
Hipskind
Philip A
PA
Aikins
James A
JA
Alvarez
Enrique
E
Cheung
Yiu-Yin
YY
Considine
Eileen L
EL
De Dios
Alfonso
A
Durst
Gregory L
GL
Ferritto
Rafael
R
Grossman
Cora Sue
CS
Giera
Deborah D
DD
Hollister
Beth A
BA
Huang
Zhongping
Z
Iversen
Philip W
PW
Law
Kevin L
KL
Li
Tiechao
T
Lin
Ho-Shen
HS
Lopez
Beatriz
B
Lopez
Jose E
JE
Cabrejas
Luisa M Martin
LM
McCann
Denis J
DJ
Molero
Victoriano
V
Reilly
John E
JE
Richett
Michael E
ME
Shih
Chuan
C
Teicher
Beverly
B
Wikel
James H
JH
White
Wesley T
WT
Mader
Mary M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology
D000970:Antineoplastic Agents; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A