Natural products with interesting biological properties and structural diversity have often served as valuable lead drug candidates for the treatment of various human diseases. Largazole, isolated from the marine cyanobacterium Symploca sp. has exhibited potent inhibitory activity against many cancer cell lines. Besides, it shows remarkable selectivity between transformed and nontransformed cells, which is the main disadvantage of other antitumor natural products such as paclitaxel and actinomycin D. Due to its potential as a potent and selective anticancer drug candidate, a great deal of attention has been focused on largazole and its analogues. It is the aim of this review to highlight synthetic aspects of largazole and its analogues as well as their preliminary structure-activity relationship studies.
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| http://dx.doi.org/10.3390/molecules16064681 | DOI Listing |
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Progress in the discovery and development of anticancer agents from marine cyanobacteria.
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Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, Florida 32610, USA.
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Mar Drugs
June 2020
School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China.
Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole's macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five-nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol.
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Promidis, Via Olgettina 60, 20132 Milano, Italy.
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School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai, 201203, China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address:
Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs.
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School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China.
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