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.

支链脂肪酸（BCFA）是一类具有良好抗癌活性的脂肪酸。BCFA 13-甲基十四烷酸（13-MTD）在体内抑制肿瘤生长而无毒性，但功效受限于中等效力，这是所有已知BCFA共有的特性。BCFAs的作用机理尚未完全阐明，在缺乏明确定义的靶标的情况下，BCFA效能的优化必须依赖于结构-活性关系。我们目前对促进BCFA抗癌活性的结构特征的理解受到所报道的BCFA的低结构多样性的限制。本研究的目的是研究两种新的结构修饰-不饱和和支链基团大小-对BCFA活性的影响。因此，饱和和顺式的同源序列合成了带有甲基，乙基，丙基和丁基支化基团的-Δ11不饱和BCFA，并在体外针对三种人类癌细胞系进行了筛选。将新BCFA的效力与13-MTD和带有顺式-Δ11双键的直链单未饱和脂肪酸（MUFA）进行了比较。出现的主要发现是，BCFA的抗癌活性受到较大分支基团的不利影响，但通过在BCFA烷基链中引入顺式-Δ11双键而显着提高了BCFA的抗癌活性。这项研究提供了新的结构-活性关系见解，可用于开发具有增强的效力和治疗潜力的BCFA。