First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme
✍ Scribed by Carballeira, Néstor M.; Cartagena, Michelle; Li, Fengyu; Chen, Zhongfang; Prada, Christopher F.; Calvo-Alvarez, Estefania; Reguera, Rosa M.; Balaña-Fouce, Rafael
- Book ID
- 120088388
- Publisher
- International Union of Pure and Applied Chemistry
- Year
- 2012
- Tongue
- English
- Weight
- 379 KB
- Volume
- 84
- Category
- Article
- ISSN
- 0033-4545
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✦ Synopsis
The fatty acids (±)-2-methoxy-6__Z__-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 (__Ld__TopIB) 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 __Ld__TopIB, with the acetylenic acid displaying an EC~50~ = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit Ld__TopIB. The (±)-2-methoxy-6__Z-heptadecenoic acid preferentially inhibited __Ld__TopIB 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 __Ld__TopIB 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 EC~50~ = 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.