TY - JOUR
T1 - A Novel Class of N-Sulfonyl and N-Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells
AU - Yong, Cassandra
AU - Devine, Shane M.
AU - Gao, Xuexin
AU - Yan, Angelina
AU - Callaghan, Richard
AU - Capuano, Ben
AU - Scammells, Peter J.
N1 - Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2019/12/4
Y1 - 2019/12/4
N2 - 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-1H-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/AdrRES cells despite high expression of the multidrug efflux pump, P-glycoprotein.
AB - 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-1H-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/AdrRES cells despite high expression of the multidrug efflux pump, P-glycoprotein.
KW - anticancer agents
KW - antimitotic agents
KW - microtubule targeting agents
KW - natural products
KW - noscapine derivatives
UR - http://www.scopus.com/inward/record.url?scp=85075212256&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201900477
DO - 10.1002/cmdc.201900477
M3 - Article
SN - 1860-7179
VL - 14
SP - 1968
EP - 1981
JO - ChemMedChem
JF - ChemMedChem
IS - 23
ER -