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Short Paper | Special issue | Vol 101, No. 2, 2020, pp.679-691
Published online, 17th September, 2019
DOI: 10.3987/COM-19-S(F)35
Synthesis of a Biphenylalanine Analogue of Apratoxin A Displaying Substantially Enhanced Cytotoxicity

Yuichi Onda, Kazuki Fukushi, Kosuke Ohsawa, Masahito Yoshida, Yuichi Masuda, and Takayuki Doi*

*Graduate School of Pharmaceutical Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan


The concise synthesis of the 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid moiety of apratoxin A and the total synthesis of compound 3, a 4-biphenylalanine (Bph) analogue of apratoxin A, have been demonstrated. The Bph analogue 3 exhibited a 16-fold increase in cytotoxicity against HCT-116 cells with respect to apratoxin A. This evidence indicated that existing the 4-phenyl group of Bph in 3 significantly enhanced its cytotoxicity, a conclusion corroborated by the 100-fold difference in cytotoxicity against HCT-116 cells observed between apratoxin M7 and apratoxin M16, which is characterized by the presence of a 4-phenyl group where apratoxin M7 displays a 4-methoxy group. Results from a conformational study using a distance geometry method suggested that 3 and apratoxin A adopt similar conformations in CD3CN.