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The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase

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Lipids

Abstract

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.

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Scheme 1
Fig. 1

Abbreviations

ABTS:

2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)

DIG:

Digoxigenin

DMSO:

Dimethyl sulfoxide

DTT:

Dithiothreitol

FA:

Fatty acids

GC-MS:

Gas chromatography-mass spectrometry

HAART:

Highly active-antiretroviral therapy

HIV:

Human immunodeficiency virus

IC50 :

Inhibitory concentration for half-life maximal inhibition

NA:

Nervonic acid

NNRTI:

Non-nucleoside reverse transcriptase inhibitors

NRTI:

Nucleoside reverse transcriptase inhibitors

PBMC:

Peripheral blood mononuclear cells

PDC:

Pyridinium dichromate

p-TSA:

p-Toluenesulfonic acid

RT:

Reverse transcriptase

THF:

Tetrahydrofuran

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Acknowledgments

Part of the work described herein was initially supported by Award Number SC1GM084708 from the National Institutes of General Medical Sciences (NIGMS) of the NIH. K. Rosado acknowledges the support of the UPR RISE program for an undergraduate fellowship. We thank Dr. Fred Strobel (Emory University) for the high resolution mass spectral data. We acknowledge the support of the National Center for Research Resources and the NIGMS of the NIH through Grant Number 5P20 GM 103475-13, the PRCTRC Grant through the Grant Numbers U54 RR026139 and 8U54MD 007587-03, and the National Institute on Minority Health and Health Disparities of the NIH through Grant Number 8G12MD007583-28 for the use of their research facilities for performing cytotoxicity tests involving PBMC.

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Authors and Affiliations

  1. Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA

    Lizabeth Giménez Moreira, Elsie A. Orellano, Karolyna Rosado & Néstor M. Carballeira

  2. 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. Guido & Adriano D. Andricopulo

  3. Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR, 00960, USA

    Gabriela Ortiz Soto & José W. Rodríguez

  4. Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR, 00919, USA

    David J. Sanabria-Ríos

Authors
  1. Lizabeth Giménez Moreira
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  2. Elsie A. Orellano
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  3. Karolyna Rosado
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  4. Rafael V. C. Guido
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  5. Adriano D. Andricopulo
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  6. Gabriela Ortiz Soto
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  7. José W. Rodríguez
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  8. David J. Sanabria-Ríos
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  9. Néstor M. Carballeira
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Correspondence to Néstor M. Carballeira.

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Moreira, L.G., Orellano, E.A., Rosado, K. et al. The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase. Lipids 50, 1043–1050 (2015). https://doi.org/10.1007/s11745-015-4064-2

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