TY - JOUR
T1 - Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents
AU - Devine, Shane M.
AU - Yong, Cassandra
AU - Amenuvegbe, Dzifa
AU - Aurelio, Luigi
AU - Muthiah, Divya
AU - Pouton, Colin
AU - Callaghan, Richard
AU - Capuano, Ben
AU - Scammells, Peter J.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/27
Y1 - 2018/9/27
N2 - A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase with an EC50 of 2.7 μM in the MCF-7 breast-cancer cell line, a 7-fold increase compared with that of noscapine (5). This molecule had similar activity (EC50 of 2.5 μM) against the resistant NCI/AdrRES cell line, demonstrating its potential to overcome or avert known resistance mechanisms, unlike current cytotoxic agents. Compound 18g was found to modify the drug-efflux activity of P-gp and, in combination studies, potentiate the antiproliferative activity of vinblastine. These results provide insights into structural modifications to noscapine that will guide future development toward more potent cytotoxic agents that are active against resistant cancer cells.
AB - A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase with an EC50 of 2.7 μM in the MCF-7 breast-cancer cell line, a 7-fold increase compared with that of noscapine (5). This molecule had similar activity (EC50 of 2.5 μM) against the resistant NCI/AdrRES cell line, demonstrating its potential to overcome or avert known resistance mechanisms, unlike current cytotoxic agents. Compound 18g was found to modify the drug-efflux activity of P-gp and, in combination studies, potentiate the antiproliferative activity of vinblastine. These results provide insights into structural modifications to noscapine that will guide future development toward more potent cytotoxic agents that are active against resistant cancer cells.
UR - http://www.scopus.com/inward/record.url?scp=85053537318&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00986
DO - 10.1021/acs.jmedchem.8b00986
M3 - Article
SN - 0022-2623
VL - 61
SP - 8444
EP - 8456
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -