Biological Effects of Modifications of the Englerin A Glycolate

被引:4
|
作者
Seenadera, Sarath P. D. [1 ]
Long, Sarah A. [1 ]
Akee, Rhone [2 ]
Bermudez, Gabriela [3 ]
Parsonage, Gregory [4 ]
Strope, Jonathan [5 ]
Peer, Cody [5 ]
Figg, W. Douglas [5 ]
Parker, Kathlyn A. [3 ]
Beech, David J. [4 ]
Beutler, John A. [1 ]
机构
[1] NCI, Mol Targets Program, Ctr Canc Res, Frederick, MD 21702 USA
[2] Leidos Biomed, FNLCR, Frederick, MD 21702 USA
[3] SUNY Stony Brook, Dept Chem, Brook, NY 11790 USA
[4] Univ Leeds, Sch Med, Leeds LS2 9JT, England
[5] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA
来源
ACS MEDICINAL CHEMISTRY LETTERS | 2022年 / 13卷 / 09期
基金
美国国家卫生研究院; 英国惠康基金;
关键词
Renal cancer; Sesquiterpenes; Englerins; TRPC4/5; Analogues; FORMAL SYNTHESIS; (-)-ENGLERIN; CYTOTOXICITY;
D O I
10.1021/acsmedchemlett.2c00258
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Modifications at the glycolate moiety of englerin A were made to explore variations at the most sensitive site on the molecule for activity in the NCI 60 screen, wherein englerin A is highly potent and selective for renal cancer cells. Replacement of the glycolate by other functionalities as well as esterification of the glycolate hydroxyl yielded compounds which displayed excellent selectivity and potency compared with the natural product. TRPC4/5 ion channel experiments with five compounds showed delayed or reduced agonism with TRPC5, at much higher concentrations than englerin A. With TRPC4, these compounds all had no effect at 10 mu M. The same compounds were not detectable in mouse serum after a single oral dose of 12.5 mg/kg. At 100 mg/kg p.o., no toxicity was observed, and blood levels were barely detectable. Intravenous administration led to toxicity but at substantially lower doses than for englerin A.
引用
收藏
页码:1472 / 1476
页数:5
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