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Solid‐Phase Synthesis and Biological Activity of a Combinatorial Cross‐Conjugated Dienone Library
Author(s) -
Kitade Makoto,
Tanaka Hiroshi,
Oe Sho,
Iwashima Makoto,
Iguchi Kazuo,
Takahashi Takashi
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500793
Subject(s) - conjugated system , chemistry , sonogashira coupling , solid phase synthesis , cyclopentenone , alkyl , stereochemistry , derivative (finance) , yield (engineering) , aldol condensation , biological activity , organic chemistry , combinatorial chemistry , in vitro , catalysis , biochemistry , palladium , materials science , peptide , polymer , financial economics , economics , metallurgy
The solid‐phase synthesis of a combinatorial cross‐conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross‐conjugated dienone system bearing two alkyl side‐chains. The cross‐conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid‐phase synthesis of the cross‐conjugated dienones involves the Sonogashira‐coupling reaction of a solid‐supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid‐supported cyclopentenone 10 in 56 % total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC 50 <0.05 μ M ). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.