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Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation
Authors:Prof?Dr Takayuki Doi  Dr Yoshitaka Numajiri  Prof?Dr Takashi Takahashi  Dr Motoki Takagi  Dr Kazuo Shin‐ya
Institution:1. Graduate School of Pharmaceutical Sciences, Tohoku University, 6‐3 Aza‐Aoba, Aramaki, Aoba, Sendai 980‐8578 (Japan), Fax: (+81)?22‐795‐6864;2. Department of Applied Chemistry, Tokyo Institute of Technology, 2‐12‐1 Ookayama, Meguro, Tokyo 152‐8552 (Japan);3. Japan Biological Informatics Consortium (JBIC), 2‐4‐7 Aomi, Koto‐ku, Tokyo 135‐0064 (Japan);4. National Institute of Advanced Industrial Science and Technology (AIST), 2‐4‐7 Aomi, Koto‐ku, Tokyo 135‐0064 (Japan)
Abstract:Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.
Keywords:cytotoxicity  peptides  solid‐phase synthesis  structure–  activity relationships  total synthesis
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