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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Lobb_Karen@Lilly.com
Karen L
KL
Lobb
Philip A
PA
Hipskind
James A
JA
Aikins
Enrique
E
Alvarez
Yiu-Yin
YY
Cheung
Eileen L
EL
Considine
Alfonso
A
De Dios
Gregory L
GL
Durst
Rafael
R
Ferritto
Cora Sue
CS
Grossman
Deborah D
DD
Giera
Beth A
BA
Hollister
Zhongping
Z
Huang
Philip W
PW
Iversen
Kevin L
KL
Law
Tiechao
T
Li
Ho-Shen
HS
Lin
Beatriz
B
Lopez
Jose E
JE
Lopez
Luisa M Martin
LM
Cabrejas
Denis J
DJ
McCann
Victoriano
V
Molero
John E
JE
Reilly
Michael E
ME
Richett
Chuan
C
Shih
Beverly
B
Teicher
James H
JH
Wikel
Wesley T
WT
White
Mary M
MM
Mader
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