INTRODUCTION The first total synthesis of ω-phenyl Δ6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16-phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6-decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6-decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z-decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the ω-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 ± 1 μM. On the other hand, among the C10 acids, the ω-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 ± 2 μM) towards A549. RESULTS Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death. CONCLUSION The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 μM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 μM) and L. infantum promastigotes (IC50 = 60- 70 μM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum ω- phenylated acid of the series.

中文翻译：

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ω-苯基Δ6脂肪酸的首次全合成及其杀人和抗癌特性。

引言描述了ω-苯基Δ6脂肪酸（FA）的第一个全合成及其细胞毒性（A549）和利什曼杀伤性（L. infantum）活性。新型的16-苯基-6-十六烷酸（1）和已知的16-苯基十六烷酸（2）分7-8步合成，总收率分别为46％和41％。还分三步进行了前所未有的10-苯基-6-癸酸（3），10-环己基-6-癸酸（4）和10-（4-甲氧基苯基）-6-癸酸（5）的合成总产量为73-76％。乙炔锂的偶联使10-苯基-6Z-癸烯酸（6）的4步合成具有100％的顺式立体化学。确定了这些新型FA对A549细胞以及婴儿乳杆菌前鞭毛体和amastigotes的细胞毒性。在ω-苯基化FA中，对A549的最佳细胞毒性显示为1，IC50为18±1μM。另一方面，在C10酸中，ω-环己酸4对A549表现出最佳的细胞毒性（IC50 = 40±2μM）。结果基于caspase-3 / 7的研究，FA均未诱导A549细胞凋亡，因此暗示其他细胞死亡机制。结论使用顶级利什曼原虫多巴尼拓扑异构酶IB（LdTopIB）抑制剂，即1和2（EC50分别在14和36μM之间），不能稳定LdTopIB和DNA之间的裂解复合物的酸进行抗虫药研究。酸1和2对婴儿乳杆菌（IC50 = 3-6μM）和婴儿乳前乳杆菌（IC50 = 60- 70μM）表现出细胞毒性，但对鼠脾细胞毒性低。我们的结果确定1为该系列的最佳ω-苯甲酸。