著者

大澤 宏祐

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.143, no.7, pp.551-557, 2023-07-01 (Released:2023-07-01)

参考文献数

29

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Naturally occurring cyclopeptides are potential middle-molecule drug candidates beyond Lipinski’s rule of five. This paper focuses on the structural determination and structure–activity relationship (SAR) study of two cyclopeptides: asperterrestide A and decatransin. The proposed asperterrestide A was synthesized by solution-phase peptide elongation, followed by macrolactamization. NMR analysis and molecular modeling studies revealed the stereochemistry at the two α-positions of amino acid residues as opposite to each other. This was further confirmed by the total synthesis of the revised asperterrestide A. SAR study of synthetic products revealed that the β-hydroxy group in the nonproteinogenic amino acid residue was not essential for its cytotoxicity. In addition, N-alkyl-enriched peptide fragments of decatransin were synthesized in solution-phase without diketopiperadine formation. The putative candidates of decatransin was synthesized by convergent peptide coupling, followed by macrocyclization under modified Mitsunobu conditions. The structure of the natural decatransin, including its absolute configuration, was determined through a comparison of spectral data and the cytotoxicity exhibited by the synthetic products.

著者

吉田 将人 大澤 宏祐 高木 基樹 広川 貴次 植草 義徳 加藤 晃一 新家 一男 夏目 徹 土井 隆行

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.53, pp.241-245, 2011-09-02

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Thielocin B1 (1), isolated from the fermentation broth of Thielavia terricola RF-143 in 1995, consists of five multi-substituted benzene rings, which are connected with a 2,2', 6,6'-biaryl ether and four ester linkages. Recently, it was found that 1 strongly inhibits protein-protein interactions (PPIs) of PAC3 homodimer (IC_<50>= 0.02 μM) without inhibition of other PPIs such as PAC1/PAC2 or TCF/P-catenin. Since we are interested in the mode of action mechanisms of 1, we performed total synthesis of 1, and docking studies by NMR and in silico analyses. The key intermediate 2,2', 6,6'-biaryl ether 4 was synthesized from 7-membered lactone 6, which was prepared by oxidative lactonization of benzophenone 7, followed by chemoselective reduction of the lactone and removal of the resulting alcohol. The side wing 5 was synthesized from aldehyde 8 via formation of 3 and its coupling by esterification. Condensation of biaryl ether 4 and 5 was smoothly performed using trifluoroacetic anhydride to afford 21 in high yield. Formylation of 21 by treatment with dichloromethyl methyl ether and AgOTf, followed by Kraus oxidation provided acid 2. Coupling of the resulting acid 2 with phenol 3 afforded 22 in 70% yield. Finally, removal of the benzyl groups by-hydrogenation furnished thielocin B1 (1), whose spectral data were in good agreement with those of the natural product.