Expansion of the structure-activity relationship of branched chain fatty acids: Effect of unsaturation and branching group size on anticancer activity.

Branched chain fatty acids (BCFAs) are a class of fatty acid with promising anticancer activity. The BCFA 13-methyltetradecanoic acid (13-MTD) inhibits tumour growth in vivo without toxicity but efficacy is limited by moderate potency, a property shared by all known BCFAs. The mechanism of action of BCFAs has not been fully elucidated, and in the absence of a clearly defined target optimisation of BCFA potency must rely on structure-activity relationships. Our current understanding of the structural features that promote BCFA anticancer activity is limited by the low structural diversity of reported BCFAs.The aim of this study was to examine the effects of two new structural modifications- unsaturation and branching group size- on BCFA activity. Thus, homologous series of saturated and cis-Δ11 unsaturated BCFAs were synthesised bearing methyl, ethyl, propyl and butyl branching groups, and were screened in vitro for activity against three human cancer cell lines. Potencies of the new BCFAs were compared to 13-MTD and an unbranched monounstaurated fatty acid (MUFA) bearing a cis-Δ11 double bond. The principal findings to emerge were that the anticancer activity of BCFAs was adversly affected by larger branching groups but significantly improved by incorporation of a cis-Δ11 double bond into the BCFA alkyl chain. This study provides new structure-activity relationship insights that may be used to develop BCFAs with improved potency and therapeutic potential.