Shaowen Cai, Furui Shi, Jiayi Chen, Min Yu, Zhixian Shi, Hairong Tang, Yang Wang
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引用次数: 0
Abstract
In this work, a series of novel dual inhibitors against both tubulin and histone deacetylase (HDAC) were designed and synthesized by integrating the natural product Millepachine with the key pharmacophore of HDAC inhibitors. Among them, compound 6 exhibited potent antiproliferative activity against 12 cancer cell lines, with IC50 values ranging from 0.020 to 0.244 μM. Mechanistic investigations revealed that compound 6 inhibited both tubulin polymerization (IC50 2.0 μM) and HDAC8 (IC50 0.110 μM), with 54-, 27- and 132-fold selectivity over HDAC1, HDAC4 and HDAC6, respectively. In an ovarian cancer xenograft mouse model, compound 6 exhibited significant inhibitory effect on tumor growth with a favorable safety profile. These findings identify compound 6 as a promising tubulin/HDAC8 dual inhibitor for further investigation.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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