Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents

Shane M. Devine, Cassandra Yong, Dzifa Amenuvegbe, Luigi Aurelio, Divya Muthiah, Colin Pouton, Richard Callaghan, Ben Capuano, Peter J. Scammells

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)8444-8456
Number of pages13
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
DOIs
Publication statusPublished - 27 Sep 2018

Cite this

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title = "Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents",
abstract = "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.",
author = "Devine, {Shane M.} and Cassandra Yong and Dzifa Amenuvegbe and Luigi Aurelio and Divya Muthiah and Colin Pouton and Richard Callaghan and Ben Capuano and Scammells, {Peter J.}",
year = "2018",
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Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents. / Devine, Shane M.; Yong, Cassandra; Amenuvegbe, Dzifa; Aurelio, Luigi; Muthiah, Divya; Pouton, Colin; Callaghan, Richard; Capuano, Ben; Scammells, Peter J.

In: Journal of Medicinal Chemistry, Vol. 61, No. 18, 27.09.2018, p. 8444-8456.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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.

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