Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam for the Synthesis of BET Inhibitor Molibresib.

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

Impacts of sex and the estrous cycle on associations between post-fear conditioning sleep and fear memory recall.

Women are at greater risk than men for developing posttraumatic stress disorder (PTSD) after trauma exposure. Sleep, especially rapid-eye-movement sleep (REMS), has been considered a contributing factor to the development of PTSD symptoms through its effects on the processing of emotional memories. However, it remains unknown if sex and sex hormones play a role in the hypothesized impact of sleep on the development of PTSD. Animal models have methodological advantages over human studies in investigating this research question; however, animal models of sleep in PTSD have been tested only with males. C57BL/6 mice (7 males and 15 females) were exposed to 15 footshocks in a footshock chamber, and 5 min after the last footshock, were returned to their home cages for telemetric electroencephalographic sleep recording. Nine to thirteen days later, mice were returned to the footshock chamber for 10 min without footshocks. Fear recall rates were computed by comparing freezing behaviors in the footshock chamber immediately after the footshocks to those during fear context reexposure. Males had significantly lower recall rates compared to metestrous females (that received footshocks on metestrus). Overall, males slept more than both proestrous females (that received footshocks on proestrus) and metestrous females during the dark period. Regression analyses revealed that average REMS episode durations after footshocks were differentially associated with recall rates across groups, such that the association was positive in males, but negative in proestrous females. Results suggest that both sex and the estrous cycle modulate the associations between REMS continuity and fear memory consolidation.

Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde.

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.

Copper-catalyzed asymmetric hydrogenation of aryl and heteroaryl ketones.

High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity.

Metabolic energy correlates of heart rate variability spectral power associated with a 900-calorie challenge.

We studied healthy males challenged with a 900 Cal test beverage and correlated EE with the raw (ms(2)) and normalized units (nu) of total power (TP), low frequency/high frequency (LF/HF) and VLF spectral power of heart rate variability (HRV). The correlations were evaluated during 20 min of normal breathing (NB, control) and 20 min of paced breathing (PB) at 12 breaths·min(-1) (0.2 Hz). EE was not significantly correlated with any of the HRV variables before the metabolic challenge. After the challenge, EE was positively correlated with LF/HF and with VLF; VLF was also positively correlated with LF/HF during both NB and PB. These findings suggest that EE may be a correlate of LF/HF and of VLF spectral power of HRV in healthy adolescent/young adult males. The association of lower resting energy expenditure with lower amounts of VLF spectral power may occur in individuals with predilections for obese phenotypes.

Association of body fat percentage and heart rate variability measures of sympathovagal balance.

AIMS: We tested the hypothesis that body fat percentage determines cardiac sympathovagal balance in healthy subjects. MAIN METHODS: Heart rate variability (HRV) measurements were made of the standard deviation of the normal-normal RR intervals (SDNN) and the low frequency/high frequency (LF/HF) ratio, from time domain and fast Fourier transform spectral analysis of electrocardiogram RR intervals during trials of uncontrolled and controlled (paced) breathing at 0.2Hz. Body fat percentage was measured by dual energy x-ray absorptiometric (DEXA) scanning. Significance of differences between uncontrolled and controlled (paced) breathing was determined by analysis of variance and correlations between body fat percentage and HRV measurements by Pearson's coefficient at P<0.05. KEY FINDINGS: Percent body fat was negatively correlated with LF/HF during the uncontrolled breathing (r=-0.56, two-tailed P<0.05, one-tailed P<0.01) but not during the paced breathing trial (r=-0.34, (P>0.1). SIGNIFICANCE: We conclude that sympathetic activity produced by paced breathing at 0.2Hz can obscure the relationship between body fat percentage and sympathovagal balance and that high body fat percentage may be associated with low sympathetic modulation of the heart rate in healthy adolescent/young adult males.

New silicon-mediated, sequential ring expansions of n-sized 2-cycloalkenones into hydroxyolefinic n + m + p medium-sized lactones: short synthesis of (-)-phoracantholide-J.

[reaction: see text] In only four steps from 2-cyclopentenone and 2-cyclohexenone, sequential three- or four-atom and then one- to three-atom ring enlargements produce nine- to 12-membered hydroxyolefinic lactones on a gram scale. 2-Cyclopentenone undergoes this serial 5 + 3 + 2 process to form 10-membered ring natural (-)-phoracantholide-J in six linear steps and 26% overall yield.

A-ring hydroxymethyl 19-nor analogs of the natural hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation.

A series 5-8 of 1- and 3-CH(2)OH 19-nor analogs of the hormone calcitriol (1) has been prepared. Surprisingly, 19-nor 1alpha-CH(2)OH analog 5a is more antiproliferative at 100 nM concentration than the corresponding regioisomeric analog 6a with the natural 1alpha-OH group, and 1alpha-CH(2)OH hybrid analog 7a is similar in antiproliferative potency to calcitriol (1) even at low nanomolar concentrations.

Potent, low-calcemic, selective inhibitors of CYP24 hydroxylase: 24-sulfone analogs of the hormone 1alpha,25-dihydroxyvitamin D3.

The new 24-phenylsulfone 4a, a low-calcemic analog of the natural hormone 1alpha,25-dihydroxyvitamin D(3), is a potent (IC(50) = 28nM) and highly selective inhibitor of the human 24-hydroxylase enzyme CYP24.