期刊
JOURNAL OF ORGANIC CHEMISTRY
卷 87, 期 15, 页码 9940-9956出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.2c00948
关键词
-
资金
- National Institutes of Health [CA216919]
Hsp90 is a molecular chaperone involved in regulating protein folding and stability, and it plays a significant role in cancer development and progression. Inhibition of Hsp90 has emerged as a promising approach for cancer treatment, but currently available inhibitors have demonstrated toxic side effects. Cruentaren A, a natural product, shows potent anticancer activity by disrupting the interactions between Hsp90 alpha and F1FO ATP synthase without inducing the pro-survival heat shock response. However, the complex structure of Cruentaren A has hindered its development as an anticancer agent.
The 90 kDa heat shock protein (Hsp90) belongs to a group of molecular chaperones that regulate homeostasis via the folding of nascent polypeptides into their biologically active proteins, many of which are involved in cancer development and progression. As a result, inhibition of Hsp90 is an exciting area of research for the treatment of cancer. However, most of the 18 Hsp90 N-terminal inhibitors evaluated in clinical trials exhibited deleterious side effects and toxicities. Cruentaren A is a natural product that manifests potent anticancer activity against various human cancer cell lines via disruption of interactions between Hsp90 alpha and F1FO ATP synthase, which does not induce the pro-survival, heat shock response, a major limitation associated with current Hsp90 inhibitors. However, the development of cruentaren A as a new anticancer agent has been hindered by its complex structure. Herein, we systematically removed the functionalities present in fragment 2 of cruentaren A and incorporated some key structural modifications from previous work, which produced 12 simplified analogues. Our studies determined that all functional groups present in fragment 2 are essential for cruentaren A's anticancer activity.
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