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Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC 50 over Mitomycin C
Author(s) -
Zheng Zhitong,
Touve Mollie,
Barnes Josue,
Reich Norbert,
Zhang Liming
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201402268
Subject(s) - mitomycin c , cyclopropane , alkylation , chemical space , chemistry , prostate cancer , computational biology , dna , electrophile , stereochemistry , combinatorial chemistry , cancer research , biology , biochemistry , drug discovery , cancer , genetics , ring (chemistry) , organic chemistry , catalysis
A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro‐cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB‐6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB‐6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis‐driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.