First Total Synthesis of ω-Phenyl Δ6 Fatty Acids and their Leishmanicidal and Anticancer Properties.
Curr Top Med Chem
; 18(5): 418-427, 2018.
Article
em En
| MEDLINE
| ID: mdl-29766807
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leishmania infantum
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Ácidos Graxos Ômega-6
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Inibidores da Topoisomerase I
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Antineoplásicos
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Antiprotozoários
Limite:
Humans
Idioma:
En
Revista:
Curr Top Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Porto Rico
País de publicação:
Emirados Árabes Unidos