Robert J. Gulakowski

Antireplicative and anticytopathic activities of prostratin, a non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV).

Prostratin, a non-tumor-promoting phorbol ester, inhibited human immunodeficiency virus (HIV)-induced cell killing and viral replication in a variety of acutely-infected cell systems. The potency and degree of cytoprotection was dependent on both viral strain and host cell type. Prostratin activated viral expression in two latently-infected cell lines, but had little or no effect on chronically-infected cell lines. Prostratin caused a dose-dependent, but reversible, decrease in CD4 expression in the CEM-SS and MT-2 cell lines. This down-regulation of CD4 was inhibited in a dose-dependent manner by the protein kinase C (PKC) antagonist, staurosporine. In addition, the cytoprotective and cytostatic effects of prostratin in CEM-SS cells acutely infected with HIV-1RF were reversed by bryostatin-1, a PKC agonist. Prostratin had no effect on reverse transcriptase or HIV-1 protease, nor did it inhibit the binding of gp120 to CD4. We conclude that prostratin inhibits HIV cytopathicity and replication through mechanism(s) involving PKC enzyme(s).

First synthesis of the antimalarial naphthylisoquinoline alkaloid dioncophylline C, and its unnatural anti-HIV dimer, jozimine C☆

Abstract The first total synthesis of dioncophylline C, a new antimalarial lead structure, is described. For the directed construction of the stereogenic biaryl axis, the ‘lactone methodology’ is applied, despite the lack of a ‘bridgehead oxygen’ function in the target molecule. Furthermore, the novel dimer of dioncophylline C, ‘jozimine C’, is prepared, by oxidative phenolic coupling of the protected natural monomer. Jozimine C displays good antimalarial activity (Plasmodium falciparum; IC50 = 0.445 μg/ml), and, in particular, represents the first unnatural dimer of a naphthylisoquinoline alkaloid with a high anti-HIV activity (HIV-1; EC50 = 27 μg/ml).

HIV inhibitory natural products. 3. Diterpenes from and

Abstract Extracts of the tropical rainforest trees Homalanthus acuminatus and Chrvsobalanus icaco were active in the NCI AIDS-antiviral screen. Diterpenes 1–4 were found in H . acuminatus , while two (6,7) were found in C . icaco . Compounds 1 and 6 were active in the anti-HIV screen; 1, 3 and 4 were previously unknown.

Octadehydromichellamine, a structural analog of the anti-HIV michellamines without centrochirality☆

Abstract The synthesis of octadehydromichellamine ( 4 ), as the fully dehydrogenated structural analog of the naturally occurring michellamines ( 1 ), is described. This derivative is the first michellamine-type quateraryl without centrochirality and thus constitutes a distinctly simplified structural michellamine analog. Key step of the total synthesis is the twofold coupling of a bis- O -triflate activated central binaphthalene building block 9 with 2 eq. of the isoquinoline boronic acid 8 , to give the quateraryl 11 , whose deprotection delivers the target molecule 4 , in an apparently stereochemically pure form. Octadehydromichellamine ( 4 ) shows a good order of anti-HIV activity and, compared with natural michellamines, enhanced antimalarial activity against Plasmodium falciparum .

HIV-Inhibitory Gallotannins from Lepidobotrys staudtii

Abstract Three galloylquinic acids, 1,3,4,5-tetra-O-galloylquinic acid (1), 3,4,5-tri-O-galloylquinic acid (2), and methyl 3,4,5-tri-O-galloylquinate (3) were isolated from the stem bark of the monotypic plant Lepidobotrys staudtii. Compound 1 protected target cells from the cytopathic effects of HIV-1 and HIV-2 and also exhibited potent inhibition of cellular DNA polymerases, as well as of the reverse transcriptases of HIV-1 and HIV-2, but not of other retroviruses tested.

Isolation and characterization of adociavirin, a novel HIV-inhibitory protein from the sponge Adocia sp.

Aqueous extracts of the New Zealand sponge Adocia sp. (Haplosclerida) displayed potent anticytopathic activity in CEM‐SS cells infected with HIV‐1. Protein fractions of the extract bound both to the viral coat protein gp120 and to the cellular receptor CD4, but not to other tested proteins. The purified active protein, named adociavirin, was characterized by isoelectric focusing, amino acid analysis, MALDI‐TOF mass spectrometry and N‐terminal sequencing. Adociavirin, a disulfide‐linked homodimer with a native molecular weight of 37 kDa, was active against diverse strains and isolates of HIV‐1, as well as HIV‐2, with EC50 values ranging from 0.4 nM to >400 nM. The anti‐HIV potency of adociavirin appears dependent on host cell type, with macrophage cultures being the most sensitive and peripheral blood lymphocytes the most resistant.