Vincent P. Gullo

Drug discovery from natural products.

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.

Avermectins, New Family of Potent Anthelmintic Agents: Isolation and Chromatographic Properties

The avermectins, a family of new anthelmintic agents, were isolated from the mycelia of Streptomyces avermitilis. Four closely related major components and four homologous minor components were separated from the complex. Solvent extraction, solvent partition, and adsorption methods were used to isolate and purify the complex; novel partition chromatography systems using Sephadex LH-20 were used to separate the components. A reverse-phase high-pressure liquid chromatography assay for the quantitative determination of all components was used extensively to monitor the purification methods.

A novel class of antitumor metabolites from the fungus Nattrassia mangiferae

Abstract Sch 49210, Sch 53514 and Sch 53516 have been isolated from a fungal culture, and identified by analysis of 2D NMR data. Two diacetylation derivatives Sch 53515 and Sch 53517 have been synthesized. These compounds demonstrate inhibitory activity of phospholipase D (PLD), and display potent activity in the antitumor invasion chamber assay.

Two novel diketopiperazines isolated from the fungus Tolypocladium sp.

Abstract Diketopiperazines, Sch 54794 and Sch 54796, have been isolated from a fungal fermentation. The structures of these compounds have been established based on spectroscopic data analysis. Sch 54794 exhibited inhibitory activity in the platelet activating factor (PAF) assay.

A new sterol sulfate, Sch 572423, from a marine sponge, Topsentia sp.

Bioassay-guided fractionation of an active fraction from a marine sponge Topsentia sp. in our marine fraction library (MFL) led to the isolation and identification of halistanol sulfate (1) and a new sterol sulfate Sch 572423 (2). Compounds 1 and 2 were identified as P2Y(12) inhibitors with IC(50) of 0.48 and 2.2 microM, respectively. The general method of purification for the MFL library and the structure elucidation of compound 2 are described.

A new fungal metabolite, Sch 202596, with inhibitory activity in the galanin receptor GALR1 assay

Abstract A novel spirocoumaranone, Sch 202596 ( 1 ), was isolated from the fermentation broth of Aspergillus sp. The isolation, structure elucidation and stereochemistry of 1 are described.

A novel microbial metabolite, activator of low density lipoprotein receptor promoter

The organic extract of the fermentation broth of a Micromonospora microorganism was found to contain SCH 351448 (1), the monosodium salt of a macrocyclic dilactone containing two identical diacids. The structure and relative stereochemistry were established by single-crystal X-ray analysis. SCH 351448 is a novel ionophoric compound and is a weak activator of low density lipoprotein receptor (LDL-R) promoter with an IC50 of 25 μM.

Two antiviral compounds from the plant Stylogne cauliflora as inhibitors of HCV NS3 protease

The 70% aq methanolic extract of the Peruvian plant Stylogne cauliflora was found to contain two novel oligophenolic compounds SCH 644343 (1) and SCH 644342 (2), which were identified as inhibitors of HCV NS3 protease. The structure of 1 and 2 was established based on high-resolution NMR studies. Compound 1 inhibited HCV NS3 protease with an IC(50) of 0.3 microM, while compound 2 showed an IC(50) of 0.8 microM.

COMPLESTATIN AND CHLOROPEPTIN I, CONDENSED AROMATIC PEPTIDES FROM TWO STRAINS OF STREPTOMYCETES

Abstract The mycelial extract of the fermentation broths from two strains of streptomycetes were found to contain complestatin and a mixture of complestatin and chloropeptin I, respectively. Extraction and detection of these compounds using identical procedures is evidence that complestatin and chloropeptin I are indeed natural products.

Further studies on the biosynthesis of the avermectins

SummaryThe biosynthesis of avermectins was studied further inStreptomyces avermitilis MA5502 by feeding experiments with labeled precursors.13C-NMR analysis of the compounds biosynthesized from [2-13C]acetate, [1,2-13C2]acetate, [3-13C]propionate and [2,3-13C2]propionate confirmed that the aglycone of avermectins is made from seven intact acetate and five propionate units. Feeding experiments with [1-13C]2-methylbutyrate and [1-13C]isobutyrate have shown that 2-methylbutyrate and isobutyrate are immediate precursors of the starter units of the polyketide chains of avermectin ‘a’ and ‘b’ components, respectively. The3H/14C doublelabeling experiments suggest that the two oleandrose moieties are derived from glucose.