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Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Bottom Line: The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours.But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM).Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA ; Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.

ABSTRACT
Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus

Synthesis and structures of curcumin A.Notes: (A) The purity analysis of curcumin by nano-LC-FTMS. (B) General step for the synthesis of curcumin A. (C) 1H-NMR spectrum of purified curcumin A in CDCl3. The spectrum was recorded on 400 MHz NMR instrument. (D) Nano-LC-FTMS analysis of curcumin A.Abbreviations: TIC, total ion current; EIC, extract ion chromatogram; rt, room temperature; h, hours; RT, reverse transcription; LC-FTMS, liquid chromatography -Fourier transform mass spectrometry; calcd, ; 1H-NMR, .
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f1-dddt-9-5051: Synthesis and structures of curcumin A.Notes: (A) The purity analysis of curcumin by nano-LC-FTMS. (B) General step for the synthesis of curcumin A. (C) 1H-NMR spectrum of purified curcumin A in CDCl3. The spectrum was recorded on 400 MHz NMR instrument. (D) Nano-LC-FTMS analysis of curcumin A.Abbreviations: TIC, total ion current; EIC, extract ion chromatogram; rt, room temperature; h, hours; RT, reverse transcription; LC-FTMS, liquid chromatography -Fourier transform mass spectrometry; calcd, ; 1H-NMR, .

Mentions: Presence of β-diketone moiety in curcumin makes it prone to decomposition at physiological pH (see structure in Figure 1A). To exclude the possibility that curcumin contained contaminants, we analyzed its composition by LC-MS analysis and did not find demethoxycurcumin or bisdemethoxycurcumin, typical contaminants (Figure 1A). To improve curcumin stability, we synthesized curcumin A (as described in Materials and methods) in which β-diketone moiety was removed (Figure 1B). Removal of the β-diketone moiety from curcumin yielded yellowish orange solid of molecular weight 327.1232 Mp 100–102°C.


Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Synthesis and structures of curcumin A.Notes: (A) The purity analysis of curcumin by nano-LC-FTMS. (B) General step for the synthesis of curcumin A. (C) 1H-NMR spectrum of purified curcumin A in CDCl3. The spectrum was recorded on 400 MHz NMR instrument. (D) Nano-LC-FTMS analysis of curcumin A.Abbreviations: TIC, total ion current; EIC, extract ion chromatogram; rt, room temperature; h, hours; RT, reverse transcription; LC-FTMS, liquid chromatography -Fourier transform mass spectrometry; calcd, ; 1H-NMR, .
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4562762&req=5

f1-dddt-9-5051: Synthesis and structures of curcumin A.Notes: (A) The purity analysis of curcumin by nano-LC-FTMS. (B) General step for the synthesis of curcumin A. (C) 1H-NMR spectrum of purified curcumin A in CDCl3. The spectrum was recorded on 400 MHz NMR instrument. (D) Nano-LC-FTMS analysis of curcumin A.Abbreviations: TIC, total ion current; EIC, extract ion chromatogram; rt, room temperature; h, hours; RT, reverse transcription; LC-FTMS, liquid chromatography -Fourier transform mass spectrometry; calcd, ; 1H-NMR, .
Mentions: Presence of β-diketone moiety in curcumin makes it prone to decomposition at physiological pH (see structure in Figure 1A). To exclude the possibility that curcumin contained contaminants, we analyzed its composition by LC-MS analysis and did not find demethoxycurcumin or bisdemethoxycurcumin, typical contaminants (Figure 1A). To improve curcumin stability, we synthesized curcumin A (as described in Materials and methods) in which β-diketone moiety was removed (Figure 1B). Removal of the β-diketone moiety from curcumin yielded yellowish orange solid of molecular weight 327.1232 Mp 100–102°C.

Bottom Line: The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours.But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM).Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA ; Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.

ABSTRACT
Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus