Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications |
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| Authors: | Xin Wang Suzhen Dong Dengke Feng Yazhou Chen Mingliang Ma Wenhao Hu |
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| Affiliation: | Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China |
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| Abstract: | We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-l-prolinal as a key step. Barbier-type allylation of N-Boc-l-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in vitro. |
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| Keywords: | Dolastatin 10 analogues Auristatins N-Terminal modification Stereoselective synthesis Dap and Dil |
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