Detoxification of electrophilic compounds by glutathione S-transferase catalysis: determinants of individual response to chemical carcinogens and chemotherapeutic drugs?

The glutathione S-transferases (GSTs) catalyze the GSH-dependent detoxification of reactive electrophiles such as genotoxic chemical carcinogens and cytotoxic chemotherapeutic agents. Allelic polymorphism in the GSTs has been used to investigate the hypothesis that GSTs are involved in susceptibility to human cancers. Such studies have resulted in low penetrance, high prevalence associations between cancer risk and GST polymorphisms. By examination of interindividual variation of GST expression it becomes clear that GST genotype alone is not an accurate predictor of GST expression. GST expression is tissue specific and interindividual variation of expression is at least 7-fold in normal tissues. Thus, populations of the same genotype are actually heterogeneous as regards expression. Similarly, polymorphisms are not effective in all tissues and GST induction is not independent of genotype. Mechanistic models for chemical aspects of colorectal cancer and chemotherapy for breast cancer demonstrate some of the ways by which such interactions can be studied and the potential for future studies.     

Phenylbutyrates as potent,orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.     

HIV-1 protease inhibitors with picomolar potency against PI-resistant HIV-1 by modification of the P1' substituent

Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility.     

Binding of beta-carbolines at 5-HT(2) serotonin receptors

A series of ring-substituted (i.e., methoxy and bromo) 3,4-dihydro- and 1,2,3,4-tetrahydro-β-carbolines was examined at 5-HT_2A and 5-HT_2C serotonin receptors. Whereas most of the methoxy-substituted derivatives typically displayed affinities similar to their unsubstituted parents, certain (particularly 8-substituted) bromo derivatives displayed enhanced affinity. A binding profile was obtained for selected β-carbolines.     

Design and synthesis of factor Xa inhibitors and their prodrugs

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.     

Mathematical modeling of the onset of capillary formation initiating angiogenesis

It is well accepted that neo-vascular formation can be divided into three main stages (which may be overlapping): (1) changes within the existing vessel, (2) formation of a new channel, (3) maturation of the new vessel. In this paper we present a new approach to angiogenesis, based on the theory of reinforced random walks, coupled with a Michaelis-Menten type mechanism which views the endothelial cell receptors as the catalyst for transforming angiogenic factor into proteolytic enzyme in order to model the first stage. In this model, a single layer of endothelial cells is separated by a vascular wall from an extracellular tissue matrix. A coupled system of ordinary and partial differential equations is derived which, in the presence of an angiogenic agent, predicts the aggregation of the endothelial cells and the collapse of the vascular lamina, opening a passage into the extracellular matrix. We refer to this as the onset of vascular sprouting. Some biological evidence for the correctness of our model is indicated by the formation of teats in utero. Further evidence for the correctness of the model is given by its prediction that endothelial cells will line the nascent capillary at the onset of capillary angiogenesis. Received: 27 May 1999 / Revised version: 28 December 1999 / Published online: 16 February 2001