Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel, small-molecule hypoxia inducible factor-1 pathway inhibitors and anticancer agents.
Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel, small-molecule hypoxia inducible factor-1 pathway inhibitors and anticancer agents.
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N-烷基-N的设计和体外活性代理商。
DOI：
10.1021/jm300752n
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发表时间：
2012-08-09
影响因子：
7.3
通讯作者：
Goodman, Mark M.
中科院分区：
文献类型：
--
作者：
Mun, Jiyoung;Jabbar, Adnan Abdul;Devi, Narra Sarojini;Yin, Shaoman;Wang, Yingzhe;Tan, Chalet;Culver, Deborah;Snyder, James P.;Van Meir, Erwin G.;Goodman, Mark M.
低氧诱导因子(HIF)途径控制肿瘤在低氧条件下对生长的适应，并介导化疗和辐射抵抗，因此是癌症的一个有吸引力的靶点。我们以前在高通量细胞实验中发现3，4-dimethoxy-N-[(2，2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide，是一种新的小分子缺氧诱导因子-1途径抑制剂，但其体内释放受到较差的水溶解性的阻碍(0.009μM在水中；logP7.4：3.7)。在这里，我们描述了十二个N-alkyl-N-[(8-R-2，2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides，的合成，通过电子计算，它们被设计为具有最佳的脂亲性和水溶解性。12个新类似物中有8个的实验logP7.4值在1.2∼3.1之间。测定了3种类似物在水中的溶解度，其中最易溶的N-[(8-methoxy-2，2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide在水中的溶解度为80μM，例如∼的溶解度提高了9000倍。药理优化对药物疗效的影响很小，因为在我们的低氧诱导因子依赖的报告实验中，这些化合物保持了IC50值等于或低于5μM。
The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, as a novel small molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; logP7.4: 3.7). Here we describe the synthesis of twelve N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g. a solubility improvement of ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay.
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影响因子：
11.2
作者：
Dang, DT;Chen, F;Dang, LH
通讯作者：
Dang, LH
影响因子：
11.5
作者：
Cao, Xianhua;Bloomston, Mark;Sun, Duxin
通讯作者：
Sun, Duxin
DOI：
10.1039/j39710000811
发表时间：
1971-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY C-ORGANIC
影响因子：
--
作者：
BANDARANAYAKE, WM;CROMBIE, L;WHITING, DA
通讯作者：
WHITING, DA
影响因子：
4.8
作者：
Eul, B;Rose, F;Hänze, J
通讯作者：
Hänze, J
影响因子：
2.1
作者：
Henry, GE;Jacobs, H
通讯作者：
Jacobs, H