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Mar. Drugs 2013, 11(10), 3661-3675; doi:10.3390/md11103661

Synthesis of Marine α-Methoxylated Fatty Acid Analogs that Effectively Inhibit the Topoisomerase IB from Leishmania donovani with a Mechanism Different from that of Camptothecin

1
Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico
2
Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, León 24071, Spain
3
Infectious Diseases Research Center of the CHUL of Québec and Laval University, Québec City, Québec G1V 4G2, Canada
*
Author to whom correspondence should be addressed.
Received: 7 August 2013 / Revised: 1 September 2013 / Accepted: 10 September 2013 / Published: 30 September 2013
(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)
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Abstract

Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5Z,9Z)-(±)-2-methoxy-5, 9-eicosadienoic acid (1) and its acetylenic analog (±)-2-methoxy-5,9-eicosadiynoic acid (2), and report that they inhibit (EC50 values between 31 and 22 µM) the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB). The inhibition of LdTopIB (EC50 = 53 µM) by the acid (±)-2-methoxy-6-icosynoic acid (12) was studied as well. The potency of LdTopIB inhibition followed the trend 2 > 1 > 12, indicating that the effectiveness of inhibition depends on the degree of unsaturation. All of the studied α-methoxylated fatty acids failed to inhibit the human topoisomerase IB enzyme (hTopIB) at 100 µM. However, the α-methoxylated fatty acids were capable of inhibiting an active but truncated LdTopIB with which camptothecin (CPT) cannot interact suggesting that the methoxylated fatty acids inhibit LdTopIB with a mechanism different from that of CPT. The diunsaturated fatty acids displayed low cytotoxicity towards Leishmania infantum promastigotes (EC50 values between 260 and 240 µM), but 12 displayed a better cytotoxicity towards Leishmania donovani promastigotes (EC50 = 100 µM) and a better therapeutic index.
Keywords: methoxylated fatty acids; leishmania donovani; 2-methoxy-5,9-eicosadienoic acid; topoisomerase IB methoxylated fatty acids; leishmania donovani; 2-methoxy-5,9-eicosadienoic acid; topoisomerase IB
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Carballeira, N.M.; Montano, N.; Alvarez-Velilla, R.; Prada, C.F.; Reguera, R.M.; Balaña-Fouce, R. Synthesis of Marine α-Methoxylated Fatty Acid Analogs that Effectively Inhibit the Topoisomerase IB from Leishmania donovani with a Mechanism Different from that of Camptothecin. Mar. Drugs 2013, 11, 3661-3675.

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