Structure-activity relationship of 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent

被引：36

作者：

Mun, Jiyoung ^{[2
]}

Jabbar, Adnan Abdul ^{[3
]}

Devi, Narra Sarojini ^{[1
]}

Liu, Yuan ^{[4
,5
]}

Van Meir, Erwin G. ^{[1
,3
,4
]}

Goodman, Mark M. ^{[2
,4
]}

机构：

[1] Emory Univ, Dept Neurosurg, Sch Med, Atlanta, GA 30322 USA

[2] Emory Univ, Dept Radiol & Imaging Sci, CSI, Wesley Woods Hlth Ctr, Atlanta, GA 30329 USA

[3] Emory Univ, Dept Hematol & Med Oncol, Sch Med, Atlanta, GA 30322 USA

[4] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA

[5] Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 14期

关键词：

Hypoxia inducible factor-1; Small molecule HIF-1 transcription factor inhibitors; Tumor hypoxia; 3,4-Dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide; Structure-activity relationships; Anti-cancer drugs; Brain cancer; CANCER-THERAPY; TUMOR-GROWTH; PRIVILEGED STRUCTURES; HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA; IDENTIFICATION; COMPLEX; VIVO;

D O I：

10.1016/j.bmc.2012.04.064

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have discovered that 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzene-sulfonamide, a novel small molecule HIF-1 pathway inhibitor, can antagonize tumor growth in animal models of cancer, but the treatment necessitates its delivery in a formulation, due to poor water solubility (<15 mu g/mL; pH 7.4), evidencing that the chemotype needs further exploration of its amenability to additional chemical modifications for ultimate optimization of function and pharmacology. As a first step towards this goal we investigated the structure-activity relationships of 15 lipophilic 2, 2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide to find out strategies of modification. A 3,4-dimethoxybenzenesulfonyl group in region 1 showed the strongest inhibition among five arylsulfonyl groups tested. The presence of propan-2-amine in region 2 conferred the strongest inhibitory effect of the compound on HIF-1 activated transcription in a reporter assay. These findings are important as they help define the structural motifs where the 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide can be chemically modified to improve its pharmacological properties towards development as a cancer therapeutic. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4590 / 4597

页数：8

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