Synthesis and pharmacological activities of novel cyclic disulfide and cyclic sulfide derivatives as hepatoprotective agents

In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound 1b (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed.     

Synthesis of novel derivatives of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols with potential anti-inflammatory and immunomodulating activities

Considerable experience has been accumulated with low dose rate (LDR) brachytherapy in the treatment of squamous cell carcinoma of the oral cavity and oropharynx, 4 cm or less in diameter. Recent analysis of large clinical series provided data indicating that modalities of LDR brachytherapy should be optimized in treating these tumours for increasing therapeutic ratio. LDR brachytherapy is now challenged by high dose rate (HDR) brachytherapy and pulsed dose rate (PDR) brachytherapy. Preliminary results obtained with the last two modalities are discussed in comparison with those achieved with LDR brachytherapy.     

Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres

The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT1 receptor (IC50 value, 10(-6)-10(-7)M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.     

Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives

Two new series of fused aza-heteroarylbisphosphonates (5, 8), which are structurally quite different from incadronate (YM175), and related compounds were synthesized and evaluated for antiresorptive activity using a parathyroid hormone(PTH)-induced hypercalcemia model in rats (PIH model). Among these compounds, several exhibited more potent antiresorptive activity than pamidronate. In particular, [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]bisphosphonic acid (5b, minodronate) was 100-fold more potent than pamidronate in not only the PIH model, but also in an immobilization bone atrophy model in rats (DA model), and was selected for clinical development. The structure-activity relationships in these new series of bisphosphonates are discussed.     

Carbohydrates and glycoconjugates biophysical methods

We describe Kaposi's sarcoma accompanied by osteomyelitis of the gum, cystic degeneration of the kidneys and E. coli sepsis in an Alsatian with very severe acquired immunodeficiency stimulated by poisoning with organophosphates. This is the first case of Kaposi's sarcoma observed in animals.     

The influence of progesterone on the antidiuretic and oxytocic activities of the posterior pituitary lobe of female rats

The course of delivery and labor, the post partum period and the postpartal condition of the newborn were reviewed in 315 obese patients with a bodyweight of 90 kg or more at delivery. The results were compared with those of a group of 315 patients with a body-weight of less than 90 kg, choosed by random and evaluated by statistic (t-test, x2-test). In the group of obese gravidae we found a significant higher rate of cases with induction of labor, protracted deliveries, breech presentation and operative deliveries. Also the rate of manual removal of the placenta, post partum uterine infections and disorders in the milk secretion was significant higher in this group. Post partum abnormal glucose tolerance tests ocurred abnormal more frequently in the obese patients. The weight of the infants of obese mothers was higher as in the control group. Significant higher were the perinatal mortality and the cases of fetal death in utero in the obese group compared to the non obese group.     

Synthesis and antiparasitic activities of amidinic azolated derivatives

The natural immunity status in different age groups was investigated. The positive rate of HI antibody under the age of 4 was less than 25%. The natural immunity level increased gradually with age and the positive rate of the antibody reached 80% among the group aged 13-25. Rate of seroconversion was 100% in any age group one month after immunization, and GMT rose from 13.33 to 243.16. It was suggested that immunogenicity of domestic attenuated live rubella vaccine BRD II was satisfactory. For the population with positive-antibody before immunization, the total GMT rose from 189.59 to 259.00 after vaccination and the difference between immunization before and after was highly significant. According to the above result, we suggested that the vaccination strategy for rubella among young children and women of child-bearing age should be implemented.     

Oxytocin analogues with combined high smooth muscle and negligible antidiuretic activities. Investigation of position 7 in neurohypophyseal hormones

The proline residue in position 7 of oxytocin occupies one of the four corner positions in the two beta turns proposed for the preferred conformation of the pituitary hormone. It has been suggested that synthetic modifications of the residues in these corner positions will yield analogues in which one or more of the biological activities of the parent hormone is highly accentuated in terms of potency relative to other activities. In a continued effort to test this hypothesis the following analogues of oxytocin were prepared: [7-glycine]oxytocin, [1-beta-mercaptopropionic acid,7-glycine]oxytocin, [7-alanine]oxytocin, and [1-beta-mercaptopropionic acid,7-alanine]oxytocin. These peptides were found to possess the following specific activities, respectively: rat uterotonic, 65 +/- 2, 355 +/- 3, 22 +/- 1, 123 +/- 4; avian vasodepressor, 5.3 +/- 0.8, 17 +/- 0.4, 4.8 +/- 0.1, 9.8 +/- 0.5; rat antidiuretic, less than0.01, 0.062, 0.081 +/- 0.01, 0.17 +/- 0.01; rat pressor, 0.3, 0.5, 0.4, 0.5 unit/mg. Thus the analogues retain high uterotonic activity but exhibit strongly diminished renal and vascular activities relative to oxytocin. Especially noteworthy is [1-beta-mercaptopropionic acid,7-glycine]oxytocin with its high uterotonic activity but very low antidiuretic and pressor activities. The activity profile of this analogue combined with the fact that it is only slowly enzymatically degraded warrants further investigations of this peptide for clinical applications.     

Synthesis and biological activity of novel thiazolidinediones

Novel compounds having a dual pharmacophore were synthesised and evaluated for their insulin sensitiser and anti-inflammatory properties in different animal models.     

Conserved themes but novel activities in recombinases and topoisomerases

OBJECTIVE: Hypertension is thought to play an important role in the pathogenesis of acromegalic cardiomyopathy. So far, hypertension has been defined by clinical measurement, with considerable variations reported concerning its prevalence in acromegalics. DESIGN: To determine the mean blood pressure (BP) values and the prevalence of hypertension in patients with active acromegaly according to non-invasive 24-hour ambulatory BP monitoring (ABPM) and to compare the data obtained with those provided by clinical measurement. PATIENTS: Forty patients with active acromegaly (22 women, 18 men, mean age 48.6 +/- 12.5 years) were included. Patients were in wash-out for antihypertensive treatment and none had been using any medical treatment for acromegaly for at least 3 months before the study. All were studied as outpatients. MEASUREMENTS: Clinical BP values were calculated as the mean of BP values obtained by standard sphygmomanometric measurement in three separate occasions. Mean 24-hour, daytime and night-time BP values were obtained by ABPM. RESULTS: The mean 24-hour BP values were lower than clinical BP values, the difference being significant for both systolic BP (SBP: 131.1 +/- 21.5 versus 136.1 +/- 16.3 mmHg, P < 0.02) and for diastolic BP (DBP: 74.6 +/- 10.6 versus 88.8 +/- 9.1 mmHg, P < 0.0001). ABPM values recorded during the daytime were 137.8 +/- 20.9 mmHg for SBP and 78.6 +/- 11.5 mmHg for DBP, the latter being significantly lower than the corresponding clinical BP values (P < 0.0001). About 60% of the patients considered hypertensive by clinical measurement were found to be normotensive by ABPM, thereby decreasing the prevalence of hypertension in this series from 42.5% to 17.5% according to ABPM (P < 0.02). In contrast, all patients defined as normotensive by clinical measurement were also normotensive by ABPM. CONCLUSIONS: Ambulatory blood-pressure monitoring indicated a lower prevalence of hypertension in acromegalic patients then usually reported, suggesting that the role of hypertension in the pathogenesis of acromegalic cardiomyopathy is commonly overestimated. We propose that ambulatory blood-pressure monitoring should be routinely proposed in acromegalics with high or borderline clinical blood pressure values although it is not useful in patients defined normotensive according to repeated clinical measurement.     

Renin-aldosterone axis and arginine-vasopressin responses to sodium depletion in camels

778 fecal samples from 29 Jordanian sheep flocks were examined for the presence of Clostridium perfringens. 252 field strains were isolated and typed by the enzyme immunosorbent assay. The presence of C. perfringens types B, C and D in Jordanian sheep was confirmed. Type D was found in 55% of the flocks examined. Types B and C were each isolated from 7% of the flocks examined. The proteinase activity of isolated type B field strains was similar to that of type B reference strains. According to the results, it does not seem to be necessary to include locally isolated C. perfringens strains in the Jordanian vaccine production.     

Effects of central administration of arginine-vasopressin on aversive memory retrieval

This study examined whether arginine-vasopressin (A-VP), given before the test would produce an improved retrieval of aversive memory, in the same way as pre-exposure to inescapable footshocks, in rats. For this purpose animals conditioned in a T-maze with appetitive (10% sucrose) and aversive (2.0 mA footshock) events were administered (intracerebroventricular) a single dose of 2.5, 5, 10 or 20 ng/rat of A-VP, 20-min before testing. In the retention test conducted with the same training apparatus 72 h after conditioning, the peptide treated rats showed a dose-dependent increase in latencies to enter the previously shocked goalarm, with the absence of such a difference in responding to the non-shocked goalarm. This differential response was not observed in saline treated rats. This effect of peptide on memory retrieval was similar to that seen following inescapable footshock in rats. These results suggest the possible involvement of central vasopressinergic mechanisms in the differential enhancement of memory of helplessness condition.     

Synthesis and antimicrobial testing of novel oxadiazolylbenzimidazole derivatives

OBJECTIVE: To chart the subtle neurological abnormalities in patients with asbestosis relative to possible development of cancer. METHODS: In 1979-81 a standardised neurological examination was made of 115 patients with asbestosis who carried a high risk of occupational cancer and their cancer morbidity was analysed 15 years later. RESULTS: Slight disturbances of unknown aetiology were found in the central nervous system (CNS) of 33 and in the peripheral nervous system (PNS) of 41 patients. Of these 17 had disturbances of both the CNS and PNS. This cohort was followed up to the end of 1994. During this time 47 of the patients developed cancer. Statistical analyses showed that disturbances of the CNS such as psycho-organic syndrome, cerebellar dysfunction, and motor disturbances of unknown origin were significantly associated with cancer, whereas no such association was found for peripheral neuropathy. Interaction between the radiological progression of asbestosis and disturbances of the CNS was an even stronger predictor of cancer. CONCLUSIONS: It seems that slight disturbances of the CNS are predictors of development of cancer. Whether or not these disturbances are manifestations of involvement of a paraneoplastic nervous system or some factor associated with progression of asbestosis remains open.     

Synthesis and protease-catalyzed hydrolysis of a novel hydrazinopeptide

In order to explore the potentiality of hydrazinopeptides as protease inhibitors, the resistance of the hydrazinopeptidic bond toward proteolysis was investigated. To this end, the novel hydrazinohexapeptide Z-Ala2-Pro-Val-hIle-Leu-OMe (1), where hIle represents hydrazinoisoleucine, was designed and synthesized together with the parent peptide Z-Ala2-Pro-Val-Ile-Leu-OMe (2). The interactions of 1 and 2 with human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) were analyzed comparatively. We observed that 1 behaved as a substrate for both elastases, without the formation of a stable acyl-enzyme as in the case of azapeptides. Compounds 1 and 2 were cleaved at the same site (-Val-parallel-NH-) with a slight delay of hydrolysis for 1 compared to 2 (kcat/KM for 1 vs. 2 decreased by a factor of 2.7 for the HLE-catalyzed hydrolysis at pH 8.0 and 25 degrees C). The presence of the hydrazinopeptide bond (-CONHNH-) in 1 reduced by a factor of 4.7 the apparent enzyme affinity without abolishing it. These results indicate that suitably designed hydrazinopeptides may represent interesting targets in the search for protease resisting pseudopeptides.     

Synthesis and antitumor activity of novel benzophenone derivatives

Novel benzophenone derivatives were synthesized and screened for cytotoxic and antitumor activity. Friedel-Crafts condensation was employed to construct the benzophenone skeleton. Among the compounds synthesized, morpholino and thiomorpholino benzophenones 3a-d exhibited potent cytotoxic activity against P388 murine leukemia and PC-6 human lung carcinoma cells in vitro, and compounds 3a, 3c, and 3j, when administered intraperitoneally, showed significant antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice.     

Synthesis and antibacterial activity of novel pyridobenzoxazine analogues

A series of novel LVFX (7) analogues bearing 4,4-dialkyl-3-aminopyrrolidines at the C-10 position of pyridobenzoxazine was synthesized and their antibacterial activities, pharmacokinetics and acute toxicities in animals were evaluated. Non-alkylated pyrrolidine derivative 26a showed greater activity than LVFX (7) against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa, but 26a possessed high acute toxicity in mice and unfavorable pharmacokinetics in rats. When compared with 26a, 4,4-dialkylated derivatives 26c, e.g. showed more potent activity against gram-positive bacteria along with an improvement of pharmacokinetics and reduction of acute toxicity. Increases in lipophilicity by alkylation on the pyrrolidine ring resulted in a good influence on the above profiles.     

Synthesis and pharmacological activities of 13-dehydro derivatives of primary prostaglandins

13-Dehydro derivatives of prostaglandin E1, E2, E3, F1 alpha and F2 alpha were synthesized. Compared with natural prostaglandins, 13-dehydro analogues were found to exhibit more potent inhibitory activity against human platelet aggregation and relaxation of guinea-pig isolated trachea, while they showed less potent activity of contraction of guinea-pig isolated ileum.     

The binding of glycoconjugates to human-milk D-galactosyltransferase

The net levels and turnover of ATP, ADP, and AMP were measured in the cortex and brainstem of thiamine deficient and control rats. In spite of a 63% decrease in pyruvate decarboxylase activity in the brainstem of severely deficient rats, metabolism of the adenine nucleotides was unaffected. These data indicate a major reserve capacity for pyruvate decarboxylase and show that the adenylate pool is not significantly altered in thiamine deficient rat brain.