Current Progresses and Trends in the Development of Progesterone Receptor Modulators.

The progesterone receptor (PR) is a ligand-activated steroid receptor in the nuclear receptor (NR) superfamily of transcription factor. Besides gynecological and obstetrical indications, the involvement/mechanism of PR in many other diseases, such as oncology, neurology, immunology, etc. has been revealed and studied in recent decades. Therapeutic agents that selectively activate or inhibit PR have been developed. PR agonists have generally been used in oral contraception and postmenopausal hormone replacement therapy (HRT), typically in combination with estrogens. PR antagonists and selective PR modulators (SPRMs) can be useful therapies for hormone dependent breast and prostate cancers, nonmalignant chronic conditions such as fibroids, and endometriosis. This review provides an overview and detailed discussions about the recent development of chemical structures of the PR ligands, their structural characteristics (particularly those contributing to their activity and selectivity), in vitro/in vivo studies and clinical trial outcomes, and the synthetic methodologies.

Is biodegradation of bitumen a source of recalcitrant naphthenic acid mixtures in oil sands tailing pond waters?

Carboxylic acids are transient metabolites during the mineralization of petroleum hydrocarbons. Crude oils, however, vary in their proportion of the hydrocarbon components. Depending on structure, some carboxylic acid metabolites resist further biodegradation and persist in aquatic systems. During the extraction of oil sands bitumen, recalcitrant carboxylic acid mixtures, collectively referred to as naphthenic acids (NAs), are released into the wastewaters. These waters also contain unrecovered bitumen from the oil sands. The unextracted bitumen is often overlooked as a possible source of the petroleum acids. The present article discusses the literature data on the biotransformation of hydrocarbons in bitumen from oil sands to the corresponding petroleum carboxylic acids. Some insight is given on the mechanism of the biodegradation process. The susceptibility to biodegradation is affected by differences in alicyclic carboxylic acids such as carbon chain length, chain branching, and the oddness or evenness of carbon chain containing the carboxylic group, positions where alkyl groups are substituted on the cyclic ring, geometrical isomerism, and number of cyclic rings.

Anaerobic biodegradation of alicyclic constituents of gasoline and natural gas condensate by bacteria from an anoxic aquifer.

The biodegradation of alicyclic compounds was studied under methanogenic and sulfate-reducing conditions in samples from a gas condensate-contaminated aquifer amended with whole gasoline. Aquifer microorganisms exhibited previously unrecognized anaerobic alicyclic hydrocarbon metabolism of a broad range of substrates at relatively rapid rates. Simple unsubstituted, methyl-substituted, and ethyl-substituted cyclopentenes, cyclopentanes and cyclohexanes were consumed without a substantial lag in the presence of sulfate, but rather less effectively under methanogenic conditions. Dimethyl-substituted cyclopentanes and cyclohexanes were biodegraded only in the presence of sulfate and a limited isomer-specific biodegradative pattern was seen. These results extend the range of hydrocarbons known to be susceptible to anaerobic decay and help indicate the patterns of alicyclic hydrocarbon biodegradation that can be expected.

Biodegradation of an alicyclic hydrocarbon by a sulfate-reducing enrichment from a gas condensate-contaminated aquifer.

We used ethylcyclopentane (ECP) as a model alicyclic hydrocarbon and investigated its metabolism by a sulfate-reducing bacterial enrichment obtained from a gas condensate-contaminated aquifer. The enrichment coupled the consumption of ECP with the stoichiometrically expected amount of sulfate reduced. During ECP biodegradation, we observed the transient accumulation of metabolite peaks by gas chromatography-mass spectrometry, three of which had identical mass spectrometry profiles. Mass-spectral similarities to analogous authentic standards allowed us to identify these metabolites as ethylcyclopentylsuccinic acids, ethylcyclopentylpropionic acid, ethylcyclopentylcarboxylic acid, and ethylsuccinic acid. Based on these findings, we propose a pathway for the degradation of this alicyclic hydrocarbon. Furthermore, a putative metabolite similar to ethylcyclopentylsuccinic acid was also found in samples of contaminated groundwater from the aquifer. However, no such finding was evident for samples collected from wells located upgradient of the gas condensate spill. Microbial community analysis of the ECP-degrading enrichment by denaturing gradient gel electrophoresis revealed the presence of at least three different organisms using universal eubacterial primers targeting 550 bp of the 16S rRNA gene. Based on sequence analysis, these organisms are phylogenetically related to the genera Syntrophobacter and Desulfotomaculum as well as a member of the Cytophaga-Flexibacter-Bacteroides group. The evidence suggests that alicyclic hydrocarbons such as ECP can be anaerobically activated by the addition to the double bond of fumarate to form alkylsuccinate derivatives under sulfate-reducing conditions and that the reaction occurs in the laboratory and in hydrocarbon-impacted environments.

Membranous nephropathy, hydrocarbon exposure and genetic variants of hydrocarbon detoxification.

Modulation of biotransformation by genetic traits may be important in determining environmentally-induced nephrotoxicity. We conducted a case-control study to investigate the role of occupational hydrocarbon exposure, along with polymorphisms of the genes coding for N-acetyltransferase 2 (NAT2) and glutathione S-transferase mu (GSTmu), in the development of idiopathic membranous glomerulonephritis (IMGN). Patients (n=36) with biopsy-proven IMGN were matched with healthy controls for age, gender, and geographical area. Lifetime hydrocarbon exposure was assessed by a validated questionnaire. The polymorphisms of the NAT2 and GSTmu genes (GSTM1) were defined by use of a polymerase chain reaction on white-cell DNA from peripheral blood. Exposure to hydrocarbons was significantly greater in patients with IMGN than in controls (mean+/-SEM hydrocarbon exposure score 11 003+/-2955.7 vs. 4352+/-1418, p<0.02). NAT2 acetylator status was identical in patients and controls with 23 (63.9%) fast and 13 (36.1%) slow acetylators in each group. GSTmu was present in 15 (41.7%) patients and 16 (44.4%) controls. While occupational exposure to hydrocarbons remains a likely factor in its pathogenesis, further work is required to identify the genetic polymorphisms that modulate the risk of IMGN.