Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues: Total synthesis and structure-cytotoxicity relationships

Hideo Kigoshi, Kiyotake Suenaga, Tsuyoshi Mutou, Takeshi Ishigaki, Toshiyuki Atsumi, Hiroyuki Ishiwata, Akira Sakakura, Takeshi Ogawa, Makoto Ojika, Kiyoyuki Yamada

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

Original languageEnglish
Pages (from-to)5326-5351
Number of pages26
JournalJournal of Organic Chemistry
Volume61
Issue number16
DOIs
Publication statusPublished - Aug 9 1996
Externally publishedYes

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Cytotoxicity
Actins
Hydroxyl Radical
Sulfones
Epoxidation
Iodides
Carbon
Polymerization
Amino Acids
Acids
aplyronine A

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues : Total synthesis and structure-cytotoxicity relationships. / Kigoshi, Hideo; Suenaga, Kiyotake; Mutou, Tsuyoshi; Ishigaki, Takeshi; Atsumi, Toshiyuki; Ishiwata, Hiroyuki; Sakakura, Akira; Ogawa, Takeshi; Ojika, Makoto; Yamada, Kiyoyuki.

In: Journal of Organic Chemistry, Vol. 61, No. 16, 09.08.1996, p. 5326-5351.

Research output: Contribution to journalArticle

Kigoshi, Hideo ; Suenaga, Kiyotake ; Mutou, Tsuyoshi ; Ishigaki, Takeshi ; Atsumi, Toshiyuki ; Ishiwata, Hiroyuki ; Sakakura, Akira ; Ogawa, Takeshi ; Ojika, Makoto ; Yamada, Kiyoyuki. / Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues : Total synthesis and structure-cytotoxicity relationships. In: Journal of Organic Chemistry. 1996 ; Vol. 61, No. 16. pp. 5326-5351.
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abstract = "The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.",
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AU - Kigoshi, Hideo

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AU - Mutou, Tsuyoshi

AU - Ishigaki, Takeshi

AU - Atsumi, Toshiyuki

AU - Ishiwata, Hiroyuki

AU - Sakakura, Akira

AU - Ogawa, Takeshi

AU - Ojika, Makoto

AU - Yamada, Kiyoyuki

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AB - The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

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