Anti-AIDS agents—XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives

Hashimoto, Fumio; Kashiwada, Yoshiki; Cosentino, L. Mark; Chen, Chin Ho; Garrett, Patricia E.; Lee, Kuo Hsiung̀

doi:10.1016/s0968-0896(97)00158-2

Cited by 103 publications

(96 citation statements)

References 16 publications

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“…DSB was synthesized and purified as previously described (13). The compound (formula weight ϭ 585 g/mol) was dissolved in dimethyl sulfoxide at a concentration of 1 mg/ml and added directly to culture medium at the desired concentrations.…”

Section: Cells and Viruses Primary Cd4mentioning

confidence: 99%

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Zhou

Yuan

Dismuke

et al. 2004

J Virol

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165

214

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Despite the effectiveness of currently available human immunodeficiency virus type 1 (HIV-1) therapies, a continuing need exists for new drugs to treat HIV-1 infection. We investigated the mechanism by which 3-O-{3,3-dimethylsuccinyl}-betulinic acid (DSB) inhibits HIV-1 replication. DSB functions at a late stage of the virus life cycle but does not inhibit the HIV-1 protease in vitro or interfere with virus assembly or release. DSB specifically delays the cleavage of Gag between the capsid (CA) and p2, resulting in delayed formation of the mature viral core and reduced HIV-1 infectivity. Replication of simian immunodeficiency virus (SIV) was resistant to DSB; however, a chimeric SIV carrying CA-p2 sequences from HIV-1 was inhibited by the drug, indicating that susceptibility to DSB maps to the CA-p2 region of the HIV-1 Gag protein. A single point mutation at the CA-p2 cleavage site of HIV-1 conferred strong resistance to DSB, confirming the target of the drug. HIV-1 strains that are resistant to a variety of protease inhibitors were sensitive to DSB. These findings indicate that DSB specifically protects the CA-p2 cleavage site from processing by the viral protease during virion maturation, thereby revealing a novel mechanism for pharmacologic inhibition of HIV-1 replication.

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Section: Cells and Viruses Primary Cd4mentioning

confidence: 99%

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Zhou

Yuan

Dismuke

et al. 2004

J Virol

Self Cite

165

214

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“…The synthesis, purification, and characterization of DSB were previously described (6). [ 3 H]dihydro-DSB was prepared by reductive hydrogenation of DSB using tritium, as previously described (16).…”

Section: Viruses and Cells 293t And P4 (Hela-cd4/ltr-lacz) Cells Wermentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Resistance to the Small Molecule Maturation Inhibitor 3- O -(3′,3′-Dimethylsuccinyl)-Betulinic Acid Is Conferred by a Variety of Single Amino Acid Substitutions at the CA-SP1 Cleavage Site in Gag

Zhou

Chen

Aiken

2006

J Virol

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The compound 3-O-(3,3-dimethylsuccinyl)-betulinic acid (DSB) potently and specifically inhibits human immunodeficiency virus type 1 (HIV-1) replication by delaying the cleavage of the CA-SP1 junction in Gag, leading to impaired maturation of the viral core. In this study, we investigated HIV-1 resistance to DSB by analyzing HIV-1 mutants encoding a variety of individual amino acid substitutions in the CA-SP1 cleavage site. Three of the substitutions were lethal to HIV-1 replication owing to a deleterious effect on particle assembly. The remaining mutants exhibited a range of replication efficiencies; however, each mutant was capable of replicating in the presence of concentrations of DSB that effectively inhibited wild-type HIV-1. Mutations conferring resistance to DSB also led to impaired binding of the compound to immature HIV-1 virions and loss of DSB-mediated inhibition of cleavage of Gag. Surprisingly, two of the DSB-resistant mutants retained an intermediate ability to bind the compound, suggesting that binding of DSB to immature HIV-1 particles may not be sufficient for antiviral activity. Overall, our results indicate that Gag amino acids L363 and A364 are critical for inhibition of HIV-1 replication by DSB and suggest that these residues form key contacts with the drug in the context of the assembling HIV-1 particle. These results have implications for the design of and screening for novel inhibitors of HIV-1 maturation.

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“…Plants defend themselves against microbial pathogens by various defense responses including production of antimicrobial proteins which are small molecular mass antimicrobial peptides (Walter, 2012;Garc´ıa-Olmedo et al, 2001). GC-MS result clearly indicated the plant of C. forskohlii root ethanol extract have following compounds, n -hexadecanoic acid have antibacterial and antifungal properties (Agoramoorthy et al, 2007), betulin anticancer activities, apoptosis (Patocka, 2003;Ramadoss et al, 2003) and anti-HIV activities (Hashimoto et al, 1997). Cedrol have aromatic (Breitmeier, 2006) and carcinogenic properties (Sabine, 1975).…”

Section: Discussionmentioning

confidence: 99%

Phytochemical investigation GC-MS analysis and <i>in vitro</i> antimicrobial activity of <i>Coleus forskohlii</i>

Rajkumar¹,

Malathi

2015

Bangladesh J Pharmacol

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The aim of this study was to investigate the phytochemical constituents, gas chromatography-mass spectrometry (GC-MS) analysis and antimicrobial activity of Coleus forskohlii. The different solvents such as ethanol, chloroform, acetone and aqueous extracts were identified pharmacologically as important bioactive compounds and their antimicrobial properties were studied. In the phytochemical investigation almost all the ethanol extract of leaf, stem and root having secondary metabolites like alkaloids, flavonoids, tannins, saponins, terpenoids, and steroids. The active constituents of the ethanol extract of C. forskohlii root was studied by GC-MS analysis. According to the antimicrobial results ethanol extract of C. froshkolii root showed highest antibacterial activity compared with stem and leaf. The highest antimicrobial activity was observed against Klebsiella pneumonia (19 mm) and Candida albicans (16 mm) in ethanol extract of root. Among the above extracts of leaf, stem and root, ethanol extract of root having antimicrobial activities due to the presence of phytoconstituents.

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Anti-AIDS agents—XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives

Cited by 103 publications

References 16 publications

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Human Immunodeficiency Virus Type 1 Resistance to the Small Molecule Maturation Inhibitor 3- O -(3′,3′-Dimethylsuccinyl)-Betulinic Acid Is Conferred by a Variety of Single Amino Acid Substitutions at the CA-SP1 Cleavage Site in Gag

Phytochemical investigation GC-MS analysis and <i>in vitro</i> antimicrobial activity of <i>Coleus forskohlii</i>

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