Otto D. Hensens

HMG CoA-reductase inhibitors

SummaryLovastatin and simvastatin are the 2 best-known members of the class of hypolipidaemic agents known as HMG CoA reductase inhibitors. Clinical experience with lovastatin includes over 5000 patients, 700 of whom have been treated for 2 years or more, and experience with simvastatin includes over 3500 patients, of whom 350 have been treated for 18 months or more. Lovastatin has been marketed in the United States for over 6 months. Both agents show substantial clinical efficacy, with reductions in total cholesterol of over 30% and in LDL-cholesterol of 40% in clinical studies. Modest increases in HDL-cholesterol levels of about 10% are also reported. Clinical tolerability of both agents has been good, with fewer than 3% of patients withdrawn from treatment because of clinical adverse experiences. Ophthalmological examinations in over 1100 patients treated with one or the other agent have revealed no evidence of significant short term (up to 2 years) cataractogenic potential. One to 2% of patients have elevations of serum transaminases to greater than 3 times the upper limit of normal. These episodes are asymptomatic and reversible when therapy is discontinued. Minor elevations of creatine kinase levels are reported in about 5% of patients. Myopathy, associated in some cases with myoglobinuria, and in 2 cases with transient renal failure, has been rarely reported with lovastatin, especially in patients concomitantly treated with cyclosporin, gemfibrozil or niacin. Lovastatin and simvastatin are both effective and well-tolerated agents for lowering elevated levels of serum cholesterol. As wider use confirms their safety profile, they will gain increasing importance in the therapeutic approach to hypercholesterolaemia and its consequences.

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.

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.

Lignans with platelet activating factor antagonist activity from magnolia biondii

Abstract Six active lignans were isolated from the flower buds of Magnolia biondii . They are liroresinol-B dimethyl ether, magnolin, pinoresinol dimethyl ether, fargesin, demethoxyaschantin and aschantin. All six lignans show antagonistic activities against platelet activating factor in the [ 3 H]PAF receptor binding assay.

Isolation and structure of nodulisporic acid A1 and A2, novel insecticides from a Nodulisporium sp.

The isolation and structure elucidation of two novel indole terpene insecticides nodulisporic acid A1(2) and A2 (3) from a Nodulisporium sp. are reported.

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.

Potent nor-triterpenoid blockers of the voltage-gated potassium channel Kv1.3 from Spachea correae

Abstract The isolation and structure elucidation of two novel nor-triterpenoid K V 1.3 potassium channel blockers correolide and dehydrocorreolide from the Costa Rican tree Spachea correae are reported.

8-O-acetylharpagide is a nonsteroidal ecdysteroid agonist.

We have identified a novel nonsteroidal ecdysteroid agonist. This compound was isolated from a methanol extract of Ajuga reptans L. (Lamiaceae) and the structure was identified by spectroscopic methods as 8-O-acetylharpagide. We have characterised this compound as an ecdysteroid agonist in a transactivation assay using beta-galactosidase as the reporter gene regulated by ecdysteroid response elements. In this assay, 8-O-acetylharpagide has an EC50 of 22 microM. The compound also competes with tritiated-ponasterone A for binding to the Drosophila ecdysteroid receptor. Finally, it induces differentiation of Drosophila Kc cells as would be expected of an ecdysteroid agonist. This iridoid glycoside is common to several plant species and may play a role in the natural defense mechanisms of plants.