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Synthesis of Nonracemic Pyrrolo‐allocolchicinoids Exhibiting Potent Cytotoxic Activity
Author(s) -
Shchegravina Ekaterina S.,
Knyazev Dmitry I.,
Beletskaya Irina P.,
Svirshchevskaya Elena V.,
Schmalz HansGünther,
Fedorov Alexey Yu.
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201601069
Subject(s) - chemistry , sonogashira coupling , domino , stereochemistry , ring (chemistry) , pyrrole , cytotoxic t cell , combinatorial chemistry , total synthesis , colchicine , catalysis , organic chemistry , palladium , biochemistry , medicine , in vitro
An efficient eight‐step semisynthetic approach towards nonracemic pyrrolo‐allocolchicinoids starting from natural colchicine was developed by exploiting Pd‐catalyzed domino Sonogashira coupling/5‐ endo ‐ dig cyclization of a 2‐iodo‐trifluoroacetanilide intermediate to build up the heterocyclic ring system. The N ‐Me substitution of the pyrrole ring enhanced the antitumor activity of the prepared molecules by 2–3 orders of magnitude. Among the active compounds, the N ‐methylated colchicinoid exhibited powerful cytotoxic and antiproliferative properties at concentrations < 1 n m .