Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.

A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50,MCF-7 < 10 µM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC50 < 5 µM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.

Effect of dilazep hydrochlorideon the Im munohistopathology of IgA nephropathy in ddY mice.

We determined the clinical and immunopathological effects of dilazep hydrochloride (dilazep) on IgA nephropathy of ddY mice. Group I (early-treatment group, n = 10) was orally treated with 300 mg/kg body weight of this drug from 12 weeks of age until 60 weeks of age, and group II (late-treatment group, n = 10) was also treated with the same dosage of this drug from 20 weeks of age until 60 weeks of age. Group III (control group, n = 10) received drinking water. On immunofluorescence, distribution and intensity of IgA and C3 depositions in glomeruli of group I and group II animals were significantly decreased as compared with those in group III. The expression of fibronectin, laminin, or type IV collagen in glomeruli was basically similar in the three groups treated with or without dilazep. On light microscopy, the expansion of glomerular mesangial areas and the average number of intraglomerular cells were markedly decreased as compared with those in group III. The levels of urinary protein excretion in groups I and II were significantly lower than those in group III (p < 0.01 and p < 0.05). These findings suggest that treatment with dilazep might improve the clinical and immunopathological findings in IgA nephropathy of ddY mice.

[The effect of the substance exin on development of microbial infections and isolation of ethylene in plants]. / Vliianie preparata ekzin na razvitie mikrobial'noi infektsii i vydelenie étilena u rastenii.

Effects of Exin on infection of tomato, potato, and cabbage plants with Pseudomonas solanacearum and Erwinia carotovora and a fungus Sclerotium rolfsii were studied. The treatment of infected plants with Exin caused no significant effect on the development of the disease. Treatment with streptomycin as a standard for comparison completely inhibited the growth of these microorganisms. Pretreatment with Exin one to eight days before infecting inhibited the development of diseases. The numbers of tomato and potato plants damaged among those infected with P. solanacearum were lower by 10 and 35% respectively. In field experiments (350 plants per variant), treatment with Exin decreased the development of wilt caused by S. rolfsii and P. solanacearum and rot caused by E. carotovora. Treatment with Exin activated the release of ethylene for not less than 30 days. Possible mechanisms of the effects of Exin are discussed.

Seasonal changes of parathyroid hormone in chronic hemodialysis patients.

We investigated various factors related to secondary hyperparathyroidism among hemodialysis patients. Subjects were 26 patients (20 men and 6 women) ranging in age from 24 to 75, treated at an ordinary hemodialysis center throughout the year 1991. The serum inorganic phosphate level and serum intact PTH level varied greatly from 2.5 to 12.5 mg/dl and from 10 to 1,102 pg/ml (normal range, 10-60 pg/ml), respectively. All patients were classified according to the serum intact PTH level into two groups: those with less than 120 pg/ml (Group I) and those with 120 pg/ml or more (Group II). The patients in Group I responded well to hemodialysis and drug therapy, but those in Group II were likely to have secondary hyperparathyroidism. In all patients in Group II, the PTH level increased markedly in the summer. This may be attributed to insufficient ingestion of calcium, vitamins, and other nutrients due to loss of appetite.