Synthesis and Evaluation of Novel alpha-Oxyalkyl-alpha,beta-Cyclohexenones as Pro-drugs for the Intracellular Delivery of Inhibitors of the Oxidoreductase Enzyme NQO1

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Abstract

The alpha-oxymethyl-alpha,beta-cyclohexenone moiety is embedded in several bioactive natural products, including 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) and the terpenoid, antheminone A. Both compounds exhibit cytotoxicity towards a variety of cancer cell lines â€Â“ a finding which has stimulated extensive scientific interest in compounds of this type. A series of mono-hydroxylated analogues of COTC and antheminone A bearing aryl side-chain substituents were synthesised and evaluated in order to study and optimise their structures to achieve better bioactivities. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a cytosolic homodimeric FAD-dependent flavoprotein that constantly overexpresses in tumour cells. The most commonly used NQO1 inhibitor, dicoumarol, has been found to have unpleasant â€Âœoff-targetâ€Â effects and a variety of novel NQO1 inhibitors have hence been designed. Several dicoumarol-based asymmetric NQO1 inhibitors previously designed by the Whitehead group were synthesised and evaluated. In order to overcome poor solubility of the NQO1 inhibitors in terms of drug delivery, they were coupled to different carriers possessing a cyclohexenone moiety as pro-drugs. A small panel of pro-drugs were synthesised and evaluated. They were designed to undergo a mechanism similar to that of COTC to release the NQO1 inhibitors and also to form alkylating agents to bind crucial biomacromolecules. The synthesised pro-drugs proved to exhibit varying levels of anti-proliferative activity against three tested cancer cell lines.

Keyword(s)

NQO1; anticancer prodrug; medicinal chemistry; organic synthesis

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