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Colchicine models: Synthesis and Antitubulin Activity of 2′‐Monosubstituted and 2′, 5‐Disubstituted 2,3,4,4′‐Tetramethoxy‐1,1′‐biphenyls. Synthesis of 4,4′, 5′, 6′‐tetramethoxy‐1,1′‐biphenyl‐2,3′‐dicarboxylic acid
Author(s) -
Itoh Yoshikuni,
Brossi Arnold,
Hamel Ernest,
FlippenAnderson Judith L.,
George Clifford
Publication year - 1989
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19890720203
Subject(s) - chemistry , methylamine , reductive amination , benzylamine , alcohol , amination , biphenyl , amine gas treating , organic chemistry , catalysis , medicinal chemistry
Reductive amination of 2,3,4,4′‐tetramethoxtybiphenyl‐2‐carbaldehyde ( 4 ) with MeNH 2 afforded methylamine 5 ( Scheme 1 ), Hydroxymethylation of amine 8 , prepared similarly from 4 by reductive amination with benzylamine followed by N ‐methylation, afforded alcohol 12 which was converted the 5‐methyl‐substituted methylamine 14 by conventional chemical reactions ( Scheme 2 ), Methylamine 14 was also obtained from ester 16 after hydroxymethylation to alcohol 17 and conventional manipulation of alcohol and ester functions ( Scheme 2 ). Both amines 5 and 14 as well as the 2′, 5‐dimethyl‐substituted biphenyl 26 prepared from the dialdehyde 25 by a Wolff ‐ Kishner reduction, did not show noteworthy activity in the tubulin binding assay or as inhibitors of tubulin polymerization ( Table ). However, the 2′ethyl‐substituted biphebyl 11 prepared from 4 by reaction with MeLi followed by dehyderation and catalytic reduction of styrene 10 ( Scheme 1 ) showed appreciable activity in both assays, coming close to that of known phenyltropolone models. The X‐ray analysis of 14 ·HCl and 11 showed significant difference in the orientation of the rings with respect to one another (Fig.) .