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.
Highlights
A selected group of marine sponges, such as Calyx podatypa, Tropsentia roquensis or Higginsia tethyoides, biosynthesize unusual α-methoxylated fatty acids with saturated, monounsaturated, and diunsaturated alkyl chains [1]
The synthesis of 1 followed the synthetic strategy previously developed in our group for this type of fatty acids and it is shown in Scheme 1 [8]
The inhibition of human topoisomerase IB enzyme (hTopIB) by acids 1 and 2 was compared to the inhibition observed for Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) and the results are shown in Table 1 and Figure 3
Summary
A selected group of marine sponges, such as Calyx podatypa, Tropsentia roquensis or Higginsia tethyoides, biosynthesize unusual α-methoxylated fatty acids with saturated, monounsaturated, and diunsaturated alkyl chains [1]. We found that the synthetic alkynoic analog (±)-2-OMe-6-heptadecynoic acid displayed a better inhibition of the enzyme with an EC50 of 17 ± 1 μM [7]. These findings led us to conclude that an alkynoic α-methoxylated fatty acid could be a more effective inhibitor of LdTopIB than an alkenoic α-methoxylated fatty acid provided that the carbon atoms in the acyl chain remain constant [7]. Taking advantage of the same synthetic route developed for 1, and based on previous findings that alkynoic fatty acids are better inhibitors of LdTopIB than alkenoic fatty acids [7], the unnatural analog (±)-2-methoxy-5,9-eicosadiynoic acid (2). Was synthesized expecting 2 to display a better inhibition of LdTopIB than 1
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