ABSTRACT
A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.
Subject(s)
Antiviral Agents/chemical synthesis , HIV-1/drug effects , Triterpenes/chemical synthesis , Triterpenes/pharmacology , Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , HIV-2/drug effects , Humans , Models, Molecular , Molecular Structure , Pentacyclic Triterpenes , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Triterpenes/chemistry , Tumor Cells, Cultured , Betulinic AcidABSTRACT
A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.
Subject(s)
Antiviral Agents/chemical synthesis , HIV-1/drug effects , Triterpenes/chemical synthesis , Triterpenes/pharmacology , Antiviral Agents/pharmacology , DNA Nucleotidyltransferases/antagonists & inhibitors , Enzyme Inhibitors , HIV Envelope Protein gp120/metabolism , HIV Protease Inhibitors , HIV-1/enzymology , Humans , Integrases , Molecular Structure , Pentacyclic Triterpenes , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Triterpenes/chemistry , Tumor Cells, Cultured , Betulinic AcidABSTRACT
A series of triterpene compounds characterized by a stringent structure-activity relationship were identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Currently studied botulinic derivatives have 50% inhibitory concentrations (IC50) against HIV-1 strain IIIB/LAI in the 10 nM range in several cellular infection assays but are inactive against HIV-2. These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes. Rather, they appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.
Subject(s)
Antiviral Agents , HIV Infections/prevention & control , HIV-1/pathogenicity , Triterpenes/pharmacology , CD4 Antigens/metabolism , Cell Line , Membrane Fusion , Pentacyclic Triterpenes , Structure-Activity Relationship , Triterpenes/chemistry , Betulinic AcidABSTRACT
Glycosylated analogues of the C-terminal heptapeptide of substance P either free or blocked on the N-terminal glutamine were synthesized in order to develop a metabolically stable peptide that would have an increased specificity for one type of receptor. Of the analogue described, (N-alpha-Boc-beta-D-Glc-p (1----5) Gln) -Gln-Phe-Phe-Gly-Leu-Met-NH2 is highly resistant to degradation on exposure to rat hypothalamic slices. This glycosylated peptide is about one third as potent as substance P in eliciting contractions of the guinea-pig ileum and is almost devoided of affinity for the 125I-Bolton Hunter-SP specific binding sites on rat brain synaptosomes.
Subject(s)
Brain/metabolism , Receptors, Neurotransmitter/metabolism , Substance P/analogs & derivatives , Animals , Biological Assay , Gastrointestinal Motility/drug effects , Guinea Pigs , Hypothalamus/metabolism , Ileum/drug effects , In Vitro Techniques , Rats , Receptors, Neurokinin-1 , Structure-Activity Relationship , Synaptosomes/metabolismABSTRACT
By 1H-NMR spectroscopy it has been shown that Substance P is largely aggregated at basic and acid pH and in saline solutions. These SP polymers dissociate rapidly by addition of pyridine and acetonitrile and slowly by addition of methanol. The difficulties previously encountered in the purification of SP and SP analogs may be attributed to this aggregation and can be overcome under disaggregating conditions. As a first application of our study we propose a reliable method for obtaining SP with good yield.
Subject(s)
Substance P , Hydrogen-Ion Concentration , Macromolecular Substances , Magnetic Resonance Spectroscopy , Protein Binding , SolutionsABSTRACT
The synthesis of two glycosylated analogs of Substance P is described. The activity of the peptides was assayed on the isolated guinea-pig ileum and their degradation was studied using rat hypothalamus slices. While glycosylation noticeably enhances the solubility of the corresponding compounds, the beta-glucopyranosyl moiety only slightly modifies the biological half-life and the bioactivity of the glycopeptides.
