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First Total Synthesis of ω-Phenyl Δ6 Fatty Acids and their Leishmanicidal and Anticancer Properties

[ Vol. 18 , Issue. 5 ]

Author(s):

Nestor M. Carballeira*, Christian Morales-Guzman, Ester Alvarez-Benedicto, Zally Torres-Martinez, Yamixa Delgado, Kai H. Griebenow, Arthur D. Tinoco, Rosa M. Reguera, Yolanda Perez-Pertejo, Ruben Carbajo-Andres and Rafael Balana-Fouce   Pages 418 - 427 ( 10 )

Abstract:


Introduction: The first total synthesis of ω-phenyl Δ6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16-phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6-decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6-decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z-decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the ω-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 ± 1 μM. On the other hand, among the C10 acids, the ω-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 ± 2 μM) towards A549.

Results: Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death.

Conclusion: The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 μM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 μM) and L. infantum promastigotes (IC50 = 60- 70 μM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum ω- phenylated acid of the series.

Keywords:

Acetylenic Fatty Acids, Cancer, Leishmaniasis, Leishmania infantum, Synthesis, Topoisomerase IB.

Affiliation:

Department of Chemistry, University of Puerto Rico, San Juan, Department of Chemistry, University of Puerto Rico, San Juan, Department of Chemistry, University of Puerto Rico, San Juan, Department of Chemistry, University of Puerto Rico, San Juan, Biochemistry and Pharmacology Department, San Juan Bautista School of Medicine, Caguas, Department of Chemistry, University of Puerto Rico, San Juan, Department of Chemistry, University of Puerto Rico, San Juan, Department of Biomedical Sciences, University of Leon, Campus de Vegazana, 24071, Leon, Department of Biomedical Sciences, University of Leon, Campus de Vegazana, 24071, Leon, Department of Biomedical Sciences, University of Leon, Campus de Vegazana, 24071, Leon, Department of Biomedical Sciences, University of Leon, Campus de Vegazana, 24071, Leon

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