Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as promising 5alpha-reductase inhibitors

Condensation of 3beta-hydroxy-16-[(4-chlorophenyl)methylene]androst-5-en-17-one (1) with hydrazine hydrate in acetic acid afforded N-acetyl pyrazoline derivative 2, while condensation of 1 with semicarbazide afforded compound 3. Also, compound 1 was treated with hydrazine hydrate in absolute methanol or ethanol to afford the corresponding alpha-methoxy (4) and alpha-ethoxy (5) derivatives, which were cyclized with etherated boron trifluoride to the pyrazoline derivative 6. The latter could be prepared directly by refluxing 1 with hydrazine hydrate in dioxane. Oxidation of compound 6 with Oppenour or Moffat oxidizing agents yielded 3-oxo-derivatives 7 and 8, respectively. On the other hand, condensation of compound 1 with substituted hydrazines, gave the corresponding 3beta-hydroxyandrostenopyrazolines 9a,b, which were oxidized using the Moffat method to give 3-oxo-androstenopyrazolines 10a,b, which were condensed with ethylene triphenyl-phosphorane in DMSO to yield 3-ethylene androstenopyrazolines 11a,b. Dehydrogenation of 9a,b with Wettestein oxidation afforded Delta4,6-diene-3-one analogues 12a,b, which were treated with chloranil to yield Delta(4,6,8(14))-tri-ene-3-one analogues 13a,b. Oppenour oxidation of 9a,b afforded Delta4-ene-3-one analogues 14a,b, which were treated with dichlorodicyanoquinone (DDQ) in dioxane to give Delta1,4,6-triene-3-one analogues 15a,b. Pharmacological screening showed that many of these compounds inhibit 5alpha-reductase activity.     

Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study

Rationale Dehydroepiandrosterone (DHEA) has been reported to enhance cognition in rodents, although there are inconsistent findings in humans.Objectives The aim of this study was to investigate the effects of DHEA administration in healthy young men on episodic memory and its neural correlates utilising an event-related potential (ERP) technique.Methods Twenty-four healthy young men were treated with a 7-day course of oral DHEA (150 mg b.d.) or placebo in a double blind, random, crossover and balanced order design. Subjective mood and memory were measured using visual analogue scales (VASs). Cortisol concentrations were measured in saliva samples. ERPs were recorded during retrieval in an episodic memory test. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the cognitive task.Results DHEA administration led to a reduction in evening cortisol concentrations and improved VAS mood and memory. Recollection accuracy in the episodic memory test was significantly improved following DHEA administration. LORETA revealed significant hippocampal activation associated with successful episodic memory retrieval following placebo. DHEA modified ERPs associated with retrieval and led to a trend towards an early differential activation of the anterior cingulate cortex (ACC).Conclusions DHEA treatment improved memory recollection and mood and decreased trough cortisol levels. The effect of DHEA appears to be via neuronal recruitment of the steroid sensitive ACC that may be involved in pre-hippocampal memory processing. These findings are distinctive, being the first to show such beneficial effects of DHEA on memory in healthy young men.     

Patients with papular urticaria have IgG antibodies to bedbug (Cimex lectularius) antigens

IgG and IgE against salivary gland proteins of bedbug (Cimex lectularius) were assessed in comparison with mosquito (Culex pipiens) and flea (Pulex irritans) antigens in the sera of papular urticaria patients (group I), siblings without papular urticaria (group IIa), patients’ parents (group IIb), and healthy controls (group III) (Immunoblotting). Anti-C. lectularius IgG was significantly recognized at 66 and 10 kDa in 40% of group I, besides others ranging from 45 to 107 kDa. Group IIa significantly reacted with 70 kDa (57.1%). Group IIb reacted with 21 and 8.5 kDa (26.7%). Sixty percent of group IIb and 100% of group III significantly identified a band of 12.5 kDa. IgG against C. pipiens was significantly recognized at a range of 18–105 kDa in group I, IIb (115, 7 kDa), and III (58, 50 kDa). Anti-P. irritans IgG was significantly recognized by group I (100, 70 kDa) and group IIa (60, 35 kDa). IgE response was confined to C. pipiens at 115 and 54 kDa in groups I and III, respectively, besides 68 and 58 kDa in group IIa. It is concluded that IgG is present against C. lectularius, C. pipiens, and P. irritans in papular urticaria and may contribute to its pathogenesis.     

DNA binding,antiviral activities and cytotoxicity of new furochromone and benzofuran derivatives

Bromination of visnagin (1) afforded 9-bromovisnagin (2) which on its alkaline hydrolysis afforded the 3-acetyl benzofuran derivative (3). The condensation of (3) with hydrazine hydrate, phenylhydrazine and/or hydroxylamine hydrochloride afforded the corresponding pyrazole derivatives (4a, b) and isoxazole derivative (4c). On the other hand, when compound 3 was condensed with some aromatic aldehydes, this yielded corresponding α, β-unsaturated keto derivatives (5a–e). Furthermore, when 1 was subjected to chlorosulfonation, the visnaginsulfonylchloride derivative 6 was afforded, which on amidation using morpholine, a sulonamido derivative (7) was obtained. Alkaline hydrolysis of the latter compound yielded 7-N-morpholinosulsamidobenzofuran (8) which was condensed with some aromatic aldehydes to yield the corresponding chalcone compounds (9a–e). Demethylation of visnagin afforded norvisnagin (10). The reaction of 10 with ethylbromoacetate in dry acetone yielded the ester benzopyran derivative (11) which reacted with hydrazine hydrate to afford the corresponding hydrazide derivative (12) and this was condensed with 3,4,5-trimethoxybenzaldehyde to give the corresponding hydrazone (13). A thaizolidinone derivative (14) was obtained by condensation of (13) with thioglycolic acid. Chloromethylation of norvisnagin afforded a 4-chloromethyl derivative (15) which reacted with different primary and secondary amines to yield the corresponding ethylamino derivative (16a, b). Moreover, mannich bases (16a, b) and (17a–c) were obtained by reacting norvisnagin with different primary and secondary amines in the presence of formalin but benzoylation of (16a, b) and (17a–c) afforded 4-oxybenzoyl derivative (18a–e). The prepared compounds were tested for their interaction with DNA; bromovisnagin 2 showed the highest affinity and compounds 6, 15, 8a, > 14, > 16b, 17a, and 16a showed moderate activity in decreasing potency. Moreover, compound 2 also was the most active as antiviral agent toward HS-I virus and compounds 6, 7, 15, 14, 16a, and 18a were found to be moderately active. CD₅₀ of the active compounds were also measured.     

The use of the EEG in measuring therapeutic drug action: focus on depression and antidepressants

A major issue in proof of concept studies and early clinical trials of novel therapeutic agents is that the active drugs can often have a relatively small additional effect compared with placebo. This is especially the case in psychiatry when we usually have no direct method of measuring the pathology underlying the disorder being studied but, rather, have to rely on the subjective assessment of psychiatric symptoms. The use of the electroencephalogram (EEG) offers two potential major means of addressing this problem. First it is able to provide direct data relating to neural activity that may be abnormal in certain disorders. As such there are opportunities for utilizing the EEG in a variety of ways as an objective outcome measure. Second there is growing evidence that in certain circumstances the EEG can be used to predict which patients are likely to respond to treatment, thus potentially increasing the power of studies by decreasing non-response rates and increasing mean changes in outcome measure. Both of these uses of the EEG are illustrated in reference to the study of mood disorders and in particular depression and its treatment with antidepressants.