The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents

Aaron James Debono, Sarah J Mistry, Angela Xie, Divya Muthiah, Jackson Ray Phillips, Sabatino Ventura, Richard Callaghan, Colin William Pouton, Benvenuto Capuano, Peter John Scammells

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6 , 9 , 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6 -position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9 -position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9 -position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF- 7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6 -ethylaminocarbonyl along with 9 -chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.
Original languageEnglish
Pages (from-to)399 - 410
Number of pages12
JournalChemMedChem
Volume9
Issue number2
DOIs
Publication statusPublished - 2014

Cite this

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title = "The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents",
abstract = "Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6 , 9 , 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6 -position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9 -position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9 -position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF- 7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6 -ethylaminocarbonyl along with 9 -chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.",
author = "Debono, {Aaron James} and Mistry, {Sarah J} and Angela Xie and Divya Muthiah and Phillips, {Jackson Ray} and Sabatino Ventura and Richard Callaghan and Pouton, {Colin William} and Benvenuto Capuano and Scammells, {Peter John}",
year = "2014",
doi = "10.1002/cmdc.201300395",
language = "English",
volume = "9",
pages = "399 -- 410",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",
number = "2",

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The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. / Debono, Aaron James; Mistry, Sarah J; Xie, Angela; Muthiah, Divya; Phillips, Jackson Ray; Ventura, Sabatino; Callaghan, Richard; Pouton, Colin William; Capuano, Benvenuto; Scammells, Peter John.

In: ChemMedChem, Vol. 9, No. 2, 2014, p. 399 - 410.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents

AU - Debono, Aaron James

AU - Mistry, Sarah J

AU - Xie, Angela

AU - Muthiah, Divya

AU - Phillips, Jackson Ray

AU - Ventura, Sabatino

AU - Callaghan, Richard

AU - Pouton, Colin William

AU - Capuano, Benvenuto

AU - Scammells, Peter John

PY - 2014

Y1 - 2014

N2 - Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6 , 9 , 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6 -position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9 -position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9 -position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF- 7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6 -ethylaminocarbonyl along with 9 -chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.

AB - Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6 , 9 , 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6 -position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9 -position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9 -position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF- 7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6 -ethylaminocarbonyl along with 9 -chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.

UR - http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300395/pdf

U2 - 10.1002/cmdc.201300395

DO - 10.1002/cmdc.201300395

M3 - Article

VL - 9

SP - 399

EP - 410

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 2

ER -