Jerrold M. Liesch

Pharmaceuticals from cultured algae

SummaryAn algae screening program, including cultured macroalgae, cultured cyanobacteria and cultured eukaryotic microalgae has been undertaken. Methods for the isolation, purification, preservation and cultivation of axenic cyanobacteria and eukaryotic cultures have been developed. Screening of these groups for biologically active components has lead to the isolation of pachydictyol and caulerpenyne from cultured macroalgae, while a series of hapalindoles and an antifungal depsipeptide have been isolated from cyanobacteria.

Isolation and structure of chaetomellic acids A and B from Chaetomella acutiseta: farnesyl pyrophosphate mimic inhibitors of ras farnesyl-protein transferase

Abstract Farnesyl-Protein transferase catalyses a post-translational modification of Ras that is obligatory for the cell transforming activity of this oncogene protein. The screening of natural products to identify inhibitors of this enzyme as a potential anticancer agents, has led to the isolation of two novel dicarboxylic acids, named chaetomellic acids from Chaetomella acutiseta, as potent and selective inhibitors which appear to be the first examples of nonphosphorous containing FPP mimics.

Structure of HC-toxin, a cyclic tetrapeptide from helminthosporium carbonum

Abstract Helminthosporium carbonum , which is pathogenic to maize, produces a metabolite, HC-toxin ( 1 ), with selective toxicity to susceptible host genotypes. Resistant genotypes and non host plants are tolerant. The structure of 1 (C21H32N4O6) was determined as cyclo [(2-amino-9,10-epoxy-8-oxodecanoyl)-alanyl-alanyl-prolyl] based upon spectral evidence.

Neocarzinostatin chromophore: Presence of a highly strained ether ring and its reaction with mercaptan and sodium borohydride

Spectroscopic evidence suggests the presence of a highly strained ether ring (Fig. 1) (possibly an epoxide) in the C12-subunit of the previously determined partial structure 2a (Fig. 2) of the major neocarzinostatin chromophore (NCS-Chrom A) which completes assignment of all the oxygens in the molecule. The main product from mercaptan treatment suggests opening of the ether ring involving the addition of one molecule of mercaptan as well as reduction of the C12-substructure, whereas a parallel two-step reduction occurs on NaBH4 treatment. Both reactions occur with rearrangement of the C12-substructure and the implication for the mechanism of action of NCS-Chrom A in DNA strand scission activity is discussed. The evidence suggests a downward revision of the molecular formula for NCS-Chrom A as well as minor components B and C by two protons.

Pramanicin, a novel antimicrobial agent from a fungal fermentation

Abstract The antimicrobial agent pramanicin ( 1 ), and a related fatty acid ( 6 ), were isolated from a corn-based solid or a lactose-containing liquid fermentation of a sterile fungus found growing in grass. The structures of these compounds were determined by a variety of spectral means including UV, IR, and NMR spectroscopy, as well as mass spectrometry. A number of chemical derivatives are also presented here. Pramanicin represents a new class of antimicrobial agents containing a highly functionalized head group and functionalized fatty side chain

The zaragozic acids: Structure elucidation of a new class of squalene synthase inhibitors

Structures of two novel fungal metabolites, zaragozic acids A (1) and B (2), characterized by a novel 2,8-dioxobicyclo[3.2.1] octane-4,6,7-trihydroxy-3,4,5-tricar☐ylic acid core, are proposed predominantly on the basis of 2D NMR.

Isolation and structure of flutimide, a novel endonuclease inhibitor of influenza virus

Abstract The isolation and structure elucidation of flutimide (1), an inhibitor of flutranscription endonuclease from Delitschia confertaspora, a new species, is reported. The novel natural product is characterized by N-hydroxyimide and exocyclic enamine functionalities.

Neocarzinostatin: Chemical characterization and partial structure of the non-protein chromophore

Abstract The molecular formula C35H35NO12 (mol.wt. 661) is proposed for the biologically active chromophoric component of neocarzinostatin. The partial structure 2 is proposed based on 1 H NMR and mass spectral data and consists, in part, of a 2,6-dideoxy-2-methylamino-galactose moiety and a naphthoic acid derivative. Special treatments required to obtain spectral data of the labile chromophore are described.

Neocarzinostatin chromophore: Presence of a cyclic carbonate subunit and its modification in the structure of other biologically active forms

Abstract On the basis of spectroscopic evidence, opening of a five-membered cyclic carbonate ring (1,3-dioxolan-2-one) in the C15-subunit of the previously determined partial structure 1 (Fig. 1) of the major neocarzinostatin chromophore (NCS-Chrom A ), is proposed to account for its base-catalyzed methanolysis to NCS-Chrom C . NCS-Chrom B , apparently an authentic natural product present as a minor component in all preparations of NCS studied, was found to be formally equivalent to the hydrolysis/decarboxylation product of the cyclic carbonate functionality in NCS-Chrom A . The mercaptan-dependent DNA strand-scission activity, equivalent for NCS-Chrom A , B and C , is independent of the integrity of the cyclic carbonate ring system and implicates a secondary site in the C15-substructure for mercaptan activation.

Structure elucidation of restricticin, a novel antifungal agent from penicillium restrictum

Abstract The structures and absolute stereochemistry of restricticin (1), its N,N-dimethyl derivative (4) and desglycyl hydrolysis product (3), isolated from Penicillium restrictum, have been determined on the basis of spectroscopic evidence. They belong to a new class of broad spectrum antifungal agents representing substituted tetrahydropyranyl ethers incorporating triene and glycyl ester side chains.