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

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,* , 1
, 2
, 3
, 2
 and 2
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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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