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A Novel Class of N ‐Sulfonyl and N ‐Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells
Author(s) -
Yong Cassandra,
Devine Shane M.,
Gao Xuexin,
Yan Angelina,
Callaghan Richard,
Capuano Ben,
Scammells Peter J.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900477
Subject(s) - noscapine , sulfonyl , chemistry , isoquinoline , efflux , stereochemistry , p glycoprotein , pharmacology , multiple drug resistance , biochemistry , biology , alkaloid , alkyl , organic chemistry , antibiotics
Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N ‐methyl group in the 6′‐position with a range of substituents, where N ‐ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N ‐sulfonyl and N ‐sulfamoyl noscapine derivatives. A number of these sulfonyl‐containing noscapinoids demonstrated improved activities compared to noscapine. (( R )‐5‐(( S )‐4,5‐Dimethoxy‐1,3‐dihydroisobenzofuran‐1‐yl)‐4‐methoxy‐6‐((1‐methyl‐1 H ‐imidazol‐4‐yl)sulfonyl)‐5,6,7,8‐tetrahydro[1,3]dioxolo[4,5‐ g ]isoquinoline) ( 14 q ) displayed sub‐micromolar activities of 560, 980, 271 and 443 nM against MCF‐7, PANC‐1, MDA‐MB‐435 and SK‐MEL‐5 cells, respectively. This antiproliferative effect was also maintained against drug‐resistant NCI/Adr RES cells despite high expression of the multidrug efflux pump, P‐glycoprotein.