Paeciloquinones A, B, C, D, E and F: new potent inhibitors of protein tyrosine kinases produced by Paecilomyces carneus. I. Taxonomy, fermentation, isolation and biological activity.

Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine kinase from the culture broth of the fungus Paecilomyces carneus P-177. The novel anthraquinones inhibit epidermal growth factor receptor protein tyrosine kinase in the micromolar range. Two compounds, paeciloquinones A and C, are potent and selective inhibitors of the v-abl protein tyrosine kinase with an IC50 of 0.4 microM. Dependent on the fermentation conditions, partially different sets of paeciloquinones may be produced. An HPLC method allows separation of all major active components.

3-Alkanoyl-5-hydroxymethyl tetronic acid homologues and resistomycin: new inhibitors of HIV-1 protease. I. Fermentation, isolation and biological activity.

In the course of a screening program for HIV-1 protease inhibiting activity, six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acids (1 approximately 6) and the known natural product resistomycin (7) were isolated from cultures of the Actinomycete strain DSM 7357. The substituted tetronic acids belong to a recently described structural class of secondary metabolites. The HIV-1 activity of resistomycin (7) has not been reported before.

Nonionic polyethylene glycol-ferrioxamine as a renal magnetic resonance contrast agent.

The MR relaxation properties of ferrioxamine-B, a chelate of iron, were investigated in vitro and in vivo to establish the potential use of the compound as a paramagnetic contrast agent. Whereas the paramagnetic relaxivity of ferrioxamine-B is such that, compared to gadolinium-DTPA (Gd-DTPA), two to three times higher concentrations are necessary to produce the same relaxation effects, the toxicity of the iron ion should be much lower because of the availability of physiological metabolic pathways. Preliminary experiments in three dogs under invasive cardiovascular monitoring demonstrated that high-dose bolus application (0.1-0.3 mmol/kg body weight) of ferrioxamine-B leads to a precipitous blood pressure drop to almost zero, lasting for several minutes. This reaction seems most likely the result of a negative inotropic effect of ferrioxamine-B. In order to reduce these side effects ferrioxamine was modified to a nonionic derivative, PEG-ferrioxamine-B. In vivo experiments with this compound did not demonstrate any substantial change in blood pressure. Dynamic MR imaging of the kidneys and the liver was performed after bolus injection of the compound in six dogs. The results indicate that PEG-ferrioxamine-B produces effects very similar to Gd-DTPA, resulting in T1-mediated signal intensity increases in the liver and in the early stages of passage through the kidneys. During the phase of medullary concentration, T2 effects seem to dominate visualization of the renal medulla. The nonionic PEG-ferrioxamine-B derivative appears to offer an alternative to gadolinium-containing chelates as an MR contrast agent.

A comparative evaluation of iron clearance models.

A comparative study of the non-iron-overloaded, bile duct-cannulated rat and of the Cebus monkey as iron-clearance models is presented. The ability of desferrioxamine, desferrithiocin, and a pyridoxal isonicotinoyl hydrazone (PIH) analogue to clear the metal from these two animals is evaluated. Data suggest that although rodents represent a viable first-line animal screen, there is no strict correspondence between the effectiveness of a chelator in rodents and that in primates. Rodent data should be interpreted carefully as it relates to potential human trials. Iron-loading response, the similarity between multiple human and Cebus serum and hematological values, and the ability to easily observe changes in behavioral patterns clearly render the Cebus monkey the best preclinical screen.

Potentiometry of Na+ in undiluted serum and urine with use of an improved neutral carrier-based solvent polymeric membrane electrode.

We present an improved Na+-selective liquid membrane electrode for measurement of Na+ concentrations in both undiluted serum and urine. The values for urinary Na+ obtained with the ion-selective electrode agree well with those obtained with the flame photometer. The correlation gives a standard residual deviation of +/- 2.7 mmol/L over the Na+ range of 25-280 mmol/L. In serum, this direct potentiometry yields Na+ concentrations 5.4% (SD 1.1%) higher than those obtained by atomic spectrometry and a standard residual deviation of +/- 1.1 mmol/L. Correction of these values for the volumes of protein and lipid leads to potentiometric values 1.2% (SD 0.7%) lower than those by flame photometry (residual standard deviation: +/- 1.0 mmol/L). Other factors that possibly contribute to this discrepancy are discussed.