Absolute configuration in 4-alkyl- and 4-aryl-3,4-dihydro-2(1H)-pyrimidones: a combined theoretical and experimental investigation.

Structural features (orientation of the carboxyl group, ring puckering), electronic absorption, and circular dichroism spectra of 4-alkyl- and 4-aryl-dihydropyrimidones 1-5 are calculated by semiempirical (AM1, INDO/S), ab initio (HF/6-31G, CIS/6-31G, RPA/6-31G), and density functional theory (B3LYP/6-31G) methods. These calculations allow an assignment of the absolute configuration by comparison of simulated and experimental CD spectra. Although the ab initio methods greatly overestimate electronic transition energies, the general appearance of the experimental CD spectra is quite nicely reproduced by these calculations. Thus, comparison of experimental with calculated CD spectra is a reliable tool for the assignment of the absolute configuration. For 4-methyl derivatives 1, the first enantiopure DHPM examples with no additional aromatic substituent, the stereochemistry at C4 provided by the theoretical results is confirmed by X-ray structure determination of the diastereomeric salt 6. Additional support is the consistent HPLC elution order found for all investigated DHPMs on a cellulose-derived chiral stationary phase.

Quantitative structure-enantioselective retention relationships for chromatographic separation of arylalkylcarbinols on Pirkle type chiral stationary phases.

Quantitative structure-retention (QSRR, retention factors log k1 and log k2 for the first and second eluted enantiomer) as well as enantioselective retention relationships (QSERR, separation factor log a) for a series of 42 chiral arylalkylcarbinols on four brush-type chiral stationary phases are derived by multiple linear regression analyses and artificial neuronal network calculations using 2D and 3D molecular descriptors including those obtained by quantum chemical calculations. Separation factors are in addition modeled by the 3D-QSAR method of comparative molecular field analysis (CoMFA). For the retention factors the LUMO energy turns out to be the most important descriptor, whereas for log a it is the hydrophobicity of the analytes. With CoMFA both the steric and electrostatic field are found to be of almost comparable significance.

The essential transfer protein TraM binds to DNA as a tetramer.

The TraM proteins encoded by F-like plasmids are sequence specific DNA binding proteins that are essential for conjugative DNA transfer. We investigated the quarternary structure and the DNA binding properties of the TraM wild-type protein of the resistance plasmid R1 and two mutant forms thereof. Size-exclusion chromatography and differential scanning calorimetry showed that purified TraM protein (amino acids 2-127) forms stable tetramers in solution. A truncated version of the protein termed TraMM26 (amino acids 2-56) forms dimers. Thus, the dimerization and tetramerization domains can be assigned to the N-terminal and C-terminal domains of TraM, respectively. Further analyses using chemical cross-linking and light scattering corroborated the preferentially tetrameric nature of the protein but also suggest that TraM has a tendency to form higher aggregates. Band-shift and fluorescence spectroscopy investigations of TraM-DNA complexes revealed that the TraM protein is also tetrameric when bound to its minimal DNA binding site. The deduced binding constant in the range of 10(8) M(-1) demonstrated a very strong binding of TraM to its preferred DNA sequence. Secondary structure analysis based on CD measurements showed that TraM is mainly alpha-helical with a significant increase in alpha-helicity (48 to 58%) upon DNA-binding, indicating an induced fit mechanism.

Determination of absolute configuration in 4-aryl-3, 4-dihydro-2(1H)-pyrimidones by high performance liquid chromatography and CD spectroscopy.

The absolute configuration of three 4-aryl-3, 4-dihydro-2(1H)-pyrimidones (Biginelli compounds, DHPMs) was established by comparison of the typical circular dichroism (CD) spectra of individual enantiomers with reference samples of known absolute configuration. The enantiomers were obtained by semipreparative separation of racemic mixtures on a Chiralcel OD-H chiral stationary phase. The method was used to establish the enantiopreference of various lipases in biocatalytic kinetic resolution experiments employing activated DHPM esters.

[Hypothalamic amenorrhea. Diagnostic and therapeutic values of pulsatile administration of gonadorelin]. / Aménorrhée hypothalamique. Intérêts diagnostique et thérapeutique de l'apport pulsatile de gonadoréline.

Hypothalamic amenorrhoea is characterized by deficiency of the pulsatile secretion of the gonadotropin-releasing hormone. In 18 patients with hypogonadotropic hypogonadism a precise topographical diagnosis could be made by pulsatile administration of this hormone using a portable pump, after failure of the simple gonadotropin-releasing hormone test (100 micrograms intravenously). In women wishing to become pregnant, this treatment proved valuable to induce ovulation, being remarkably effective (17 pregnancies in 20 women (85 p. 100) and 2.2 cycles/pregnancy), easy to perform, and safe, as well as less expensive and with less risk of hyperstimulation and multiple pregnancies than the conventional treatment with gonadotropins.

[Pregnancy, diabetes and the insulin pump. A better prognosis?]. / Grossesse, diabète et pompe à insuline. Un meilleur pronostic?

The fetal prognosis in pregnancy in a diabetic woman depends mainly on the blood sugar equilibrium of the mother that can be obtained, since the normal range lessens the chances of fetal abnormalities. This has been demonstrated in this series, since a system that uses the continuous automatic administration of insulin has been used. Six diabetic women were treated with continuous subcutaneous perfusion of insulin in the second half of pregnancy. The quality of the maternal blood sugar equilibrium has been proved by the normal values of glycosylated haemoglobin and the values of venous blood sugar which were always within the mean of the normal range. The tolerance of the technique is excellent (83 days in mean without a single complication). In 4 out of the 6 cases the baby was born at the 38th week of pregnancy and studies show that there was no increase in weight and a very low level of neonatal hypoglycaemia. It seems desirable to use this kind of insulin therapy which should help to contribute to a better fetal prognosis in diabetic pregnancies.

[Amenorrhea and the pill]. / L'amenorrhee de la pilule.

PIP: Postpill amenorrhea has been variously defined as amenorrhea alone or accompanied by galactorrhea and lasting from 3-6 months after termination of oral contraceptive (OC) use. According to the definition employed, postpill amenorrhea appears to affect from 2-12% of pill users. About 15% of all secondary amenorrhea appears to follow pill use. Some cases of apparent postpill amenorrhea may be due to other causes, such as pregnancy, precocious menopause, Stein-Levanthal syndrome, or tumors, and may be discovered coincidentally on discontinuation of OCs. Cases of amenorrhea with or without galactorrhea accompanied by hyperprolactinemia and of amenorrhea with normal prolactin levels should be differentiated and their etiology evaluated separately. 100 young women using OCs were divided into 3 groups according to the ethinyl estradiol (EE) content of their pills and evaluated for prolactin levels. Average prolactin levels increased significantly in high dose pills, but remained within normal limits. Prolactin secretion was found to increase with duration of pill use in all 3 groups. The mechanism of action of estrogens on prolactin appears to depend on dopaminergic antagonists, which act directly on the pituitary. Ideally, ovulation should be reestablished 3-4 weeks after termination of OC use, with the only anomaly being a slightly longer follicular phase. However, most women ovulate 2-3 months after cessation of oral contraception. In the case of postpill amenorrhea, the plasma level of 17-beta estradiol is normal, but follicle stimulating hormone and luteinizing hormone do not become elevated. The 17-beta estradiol therefore does not fill its positive feedback role but instead exercises an excessive negative feedback. Clomiphene citrate, an antiestrogenic, can often liberate the pituitary from the inhibition. Age, obstetric antecedents, and duration of OC use do not appear related to postpill amenorrhea, but late menarche, irregular menstruation before pill use, estrogen dose, excessive weight loss, smoking, poor hygiene, psychological problems, and use of other drugs are associated with higher^ieng