The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase.
The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58% overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43% overall yields. The ∆(5) acids displayed the best IC50's (24-38 µM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 µM). The ∆(9) acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 µM and the 9-pentacosynoic acid not inhibiting the enzyme at all. Fatty acid chain length and position of the unsaturation was important for the observed inhibition. None of the synthesized fatty acids were toxic (IC50 > 500 µM) towards peripheral blood mononuclear cells. Molecular modeling studies indicated the structural determinants underlying the biological activity of the most potent compounds. These results provide new insights into the structural requirements that must be present in fatty acids so as to enhance their inhibitory potential towards HIV-RT.
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
Lizabeth Giménez
LG
Moreira
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
Elsie A
EA
Orellano
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
Karolyna
K
Rosado
Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Avenida João Dagnone 1100, Jardim Santa Angelina, São Carlos, SP, 13563-120, Brazil.
Rafael V C
RV
Guido
Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Avenida João Dagnone 1100, Jardim Santa Angelina, São Carlos, SP, 13563-120, Brazil.
Adriano D
AD
Andricopulo
Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR, 00960, USA.
Gabriela Ortiz
GO
Soto
Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR, 00960, USA.
José W
JW
Rodríguez
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR, 00919, USA.
David J
DJ
Sanabria-Ríos
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA. nestor.carballeira1@upr.edu.
Néstor M
NM
Carballeira
D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008958:Models, Molecular; D013329:Structure-Activity Relationship
C000606297:5-pentacosenoic acid; C000606298:5-pentacosynoic acid; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
Fatty acids; Human immunodeficiency virus; Pentacosenoic acid; Reverse transcriptase; Synthesis