The structure activity relationships of noscapine related compounds and their pharmacological evaluation

by Aaron James DeBono

Institution: Monash University
Department: Department of Medicinal Chemistry
Year: 2015
Keywords: Noscapine; Opiates; N-demethylation; Anti-cancer
Record ID: 1044657
Full text PDF: http://arrow.monash.edu.au/hdl/1959.1/1170401


The opium poppy, Papaver somniferum, is the primary source of analgesic opiate alkaloids such as morphine. Many of the estimated 30 or more alkaloids extracted from Papaver somniferum have significant pharmaceutical value. Noscapine constitutes a low percentage of the alkaloid content of opium and has been used as a cough suppressant in humans. Current research has implicated noscapine in the ability to suppress the proliferation of various metastatic cellular lines within in vitro models. This thesis focuses on the design and synthesis of novel compounds to probe the emerging SAR of Noscapine related compounds. Recent literature reported the synthesis of N-carbamoyl/N-thiocarbamoyl analogues of noscapine but the biological activity for this series of compounds was not published. To understand whether any potential activity existed at the amine moiety, we generated a small series of N-substituted analogues, looking at various urea, thiourea, carbamate, acyl and alkyl functional groups, which were assessed for their anti-microtubule activity. From the compounds synthesized in this initial series of N-substituted analogues the N-ethyl cyclic ether noscapine analogue showed activity against both PC3 and MCF-7 cancer cell lines with an EC50 of 6.7 and 3.58 μM. We were unable to demonstrate the activity of noscapine in either cellular line (Chapter 2). Chapter 2 was published in ChemMedChem 2012, 7, 2122−2133. In Chapter 3 we explore the SAR of the noscapine scaffold further. Current published literature examined modifications at the 7- and 9′-position separately on the noscapine scaffold. These two independent modifications of the noscapine core demonstrated improvements in activity could be achieved through the chemical manipulation of different sites on the noscapine core. This resulted in a number of different analogues showing similar in vitro anti-microtubule activity. This chapter focused on the synthesis of noscapine analogues, which comprised multiple modifications on the same noscapine core to determine whether activity could be further improved. The findings from our work demonstrated that the activity of noscapine derivatives could be improved through the introduction of multiple modifications on the same core. Chapter 3 was published in ChemMedChem 2014, 9, 399−410. In Chapter 4 we explore the idea of exchanging the phthalide ring system for an isoindolinone ring system. The idea of isosteric replacement is a common concept in drug discovery and design. Bioisosteres are substituents or groups, which possess similar chemical and physical properties, but may introduce profound effects on the biological activity of the compound without making significant changes to the overall chemical structure. Chapter 4 examines the synthesis of a noscapine mimetic, and the installation of an isoindolin-1-one moiety entailing of the exact substitution pattern of the noscapine phthalide. The isoindolin-1-one could be further derivatised and/or reduced to the isoindoline moiety. Introduction of a new amine moiety facilitates a…