Abstract
Unified synthesis of FD-891 analogs and their structure–activity relationship are described. By using stereoselective allylation/crotylation and Evans aldol chemistry, six side-chain fragments having different length and terminus were synthesized. These fragments were coupled with a macrolactone fragment, improved synthesis of which was also developed here, to generate FD-891 and five truncated analogs. These synthetic compounds as well as three analogs obtained from fermentation of gene-disrupted Streptomyces graminofaciens mutants were tested for in vitro cytotoxic activity against HeLa cells. As a result, coexistence of the C8–C9 epoxide and side-chain terminus was found to be critical for the cytotoxic activity.
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Acknowledgements
We acknowledge Prof. Masahiro Terada and Mr. Takuto Yamanaka (Graduate School of Science, Tohoku University) for kindly providing information on the organocatalytic allylation using catalyst 35. This work was supported by a Grant-in-Aid for Scientific Research on the Innovative Area ‘Chemical Biology of Natural Products’ from The Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 23102013 to NK), and a Research Fellowship Grant for Young Researchers from Japan Society for the Promotion of Science (15J03635 to AK).
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Dedicated to Professor Amos B. Smith, III in celebration of his 50 years of contributions to the chemical sciences.
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Itagaki, T., Kawamata, A., Takeuchi, M. et al. Synthesis and structure–activity relationship study of FD-891: importance of the side chain and C8–C9 epoxide for cytotoxic activity against cancer cells. J Antibiot 69, 287–293 (2016). https://doi.org/10.1038/ja.2015.148
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DOI: https://doi.org/10.1038/ja.2015.148
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