Novobiocin: Redesigning a DNA Gyrase Inhibitor for Selective Inhibition of Hsp90
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- 作者：Joseph A. Burlison ; Len Neckers ; Andrew B. Smith ; Anthony Maxwell ; Brian S. J. Blagg ;
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- 刊名：Journal of the American Chemical Society
- 出版年：2006
- 出版时间：December 6, 2006
- 年：2006
- 卷：128
- 期：48
- 页码：15529 - 15536
- 全文大小：212K
- 年卷期：v.128,no.48(December 6, 2006)
- ISSN：1520-5126
文摘
Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitorof DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at~700 
M. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library ofnovobiocin analogues was prepared and initial structure-activity relationships revealed. These datasuggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendagewere detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin(DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90.Both compounds were significantly more potent than the natural product, and DHN2 proved to be moreactive than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition,these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reductionin gyrase activity. Thus, we have established the first set of compounds that clearly differentiate betweenthe C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selectiveHsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family ofantibiotics.
M. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library ofnovobiocin analogues was prepared and initial structure-activity relationships revealed. These datasuggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendagewere detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin(DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90.Both compounds were significantly more potent than the natural product, and DHN2 proved to be moreactive than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition,these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reductionin gyrase activity. Thus, we have established the first set of compounds that clearly differentiate betweenthe C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selectiveHsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family ofantibiotics.