First total synthesis of the (&plusmn;)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the <em>Leishmania</em> topoisomerase IB enzyme

Carballeira, Néstor M.; Cartagena, Michelle; Li, Fengyu; Chen, Zhongfang; Prada, Christopher F.; Calvo-Alvarez, Estefania; Reguera, Rosa M.; Balaña-Fouce, Rafael

doi:10.1351/PAC-CON-11-10-21

Pure Appl. Chem., 2012, Vol. 84, No. 9, pp. 1867-1875

http://dx.doi.org/10.1351/PAC-CON-11-10-21

Published online 2012-04-29

First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme

Néstor M. Carballeira¹*, Michelle Cartagena¹, Fengyu Li¹, Zhongfang Chen¹, Christopher F. Prada², Estefania Calvo-Alvarez², Rosa M. Reguera² and Rafael Balaña-Fouce²

¹ Department of Chemistry, University of Puerto Rico, Rio Piedras campus, P.O. Box 23346, San Juan, Puerto Rico
² Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, 24071 León, Spain

Abstract: The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited LdTopIB, with the acetylenic acid displaying an EC₅₀ = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit LdTopIB. The (±)‑2‑methoxy-6Z-heptadecenoic acid preferentially inhibited LdTopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC₅₀ = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C_17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.