Novel imidazole substituted 6-methylidene-penems as broad-spectrum beta-lactamase inhibitors

Beta-lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against beta-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of beta-lactam antibiotics ineffective in certain cases. To overcome resistance to beta-lactam antibiotics, several beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with beta-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved beta-lactamase inhibitors. Although the commercially available beta-lactamase inhibitor/beta-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum beta-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various beta-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.     

2-Alkylsulfanyl estrogen derivatives: synthesis of a novel class of multi-targeted anti-tumour agents

A flexible, direct, high yielding synthesis of 2-alkylsulfanyl estrogens from estrone has been developed. 2-Methylsulfanyl estradiol (2-MeSE2) 7 displays a similar anti-proliferative activity to the established 2-methoxyestradiol (2-MeOE2) 1, whilst its 3-O-sulfamate derivative (2-MeSE2MATE) 9 exhibits greatly enhanced anti-proliferative activity, combined with significant inhibition of steroid sulfatase, an enzyme target for the treatment of hormone-dependent tumours.     

A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity

The role of aromatase inhibitors in the treatment of hormone-dependent breast cancer is well established. However, it is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. To explore the potential advantage of dual inhibition by a single agent, we recently developed a series of dual aromatase-sulphatase inhibitors (DASIs) based on the aromatase inhibitor YM511. We report here a new structural class of DASI obtained by obtained introducing the pharmacophore for STS inhibition, i.e. a phenol sulphamate ester into another established aromatase inhibitor letrozole. Hence, the bis-sulphamate 9 was synthesised which exhibited IC(50) values of 3044 nM for aromatase and >10 microM for STS in JEG-3 cells. However, at a single oral dose of 10mg/kg, 9 inhibited aromatase and rat liver STS by 60% and 88%, respectively, 24h after administration. A proposed metabolite of 9, carbinol 10, was synthesised. Despite also showing weak STS inhibition in JEG-3 cells, 10 inhibited rat liver STS activity to the same extent as 9 at a single oral dose of 10mg/kg. Thus, the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.     

Abnormal Signal‐Averaged Electrocardiogram (SAECG) in Obesity

Objective: The occurrence of small high‐frequency electrocardiogram (ECG) potentials (1 to 20 μV) seen at the end of the QRS complex and into the ST segment have been correlated with increased risk for ventricular arrhythmias and sudden cardiac death. Computer‐assisted analysis of these “late potentials” by signal‐averaged electrocardiography (SAECG) has been studied and utilized to predict the likelihood of ventricular arrhythmias in various clinical states. Obesity is associated with significant cardiovascular morbidity and sudden death. Ventricular arrhythmias are postulated causes. We studied the occurrence of late potentials in a randomly selected group of obese patients and healthy volunteers. Research Methods and Procedures: We performed SAECG on 105 subjects. Of these, 62 were obese ambulatory patients with body mass index (BMI) of >30 kg/m², whereas 43 were healthy asymptomatic volunteers with a BMI of <30 kg/m². Patients with a history of clinical heart disease and pulmonary disease, electrolyte abnormalities, recent hospitalizations, or abnormal screening ECG or taking medications known to alter the QRS interval were excluded. At least 250 beats were analyzed with a noise level of <0.50 μV. Criteria of a late potential include QRS duration >114 ms, high‐frequency low amplitude >38 ms, and root‐mean‐square voltage <20 μV. Patients were divided into four subgroups based on BMI values. The prevalence of SAECG abnormalities in each BMI subgroup was studied. We utilized multiple logistic regression analysis to study the effect of obesity, hypertension, and diabetes mellitus on abnormal SAECG results. Results: Compared to age‐ and sex‐matched healthy volunteers with BMI of <30 kg/m², obese patients with BMI of >30 kg/m² had significantly more abnormalities on SAECG (4.6% vs. 55%). In the obese group, the prevalence and number of abnormalities increased with increase in BMI (35% in the BMI 31 to 40 kg/m² subgroup, 86% in the BMI 41 to 50 kg/m² subgroup, and 100% in patients with BMI of >50 kg/m²). Multiple logistic regression analysis shows that BMI is an independent predictor variable of abnormal SAECG results in obese patients (n = 62) with BMI of >30kg/m² as well as in all study subjects (n = 105). BMI also predicts abnormality of each abnormal SAECG criterion in both obese and all subjects. Hypertension was found to influence the QRS duration alone in obese and all subjects. Discussion: Obesity is associated with increased occurrence of abnormal SAECG results. These abnormalities are found both in obese patients with and without hypertension and/or diabetes. Obesity is an independent predictor variable of abnormal SAECG results. A history of hypertension predicts abnormality of QRS duration only.     

Determination of centpropazine and its metabolite in rat serum by high-performance liquid chromatography and fluorescence detection

A new HPLC assay method was developed for the simultaneous assay for centpropazine (antidepressant) and its hydroxylated metabolite (II) to assess their pharmacokinetics and metabolism characteristics. Rat serum samples were extracted with ether, backwashed with n-hexane and injected onto the HPLC system, which used a C₁₈ column, gradient elution and fluorescence detection at 250 Ex/350 nm Em. Variations in intra- and inter-batch accuracy and precision were within acceptable limits of <±20% at low and <±15% at higher concentrations. Samples were stable in autosampler prior to injection and after multiple freeze–thaw cycles. Linearity was observed between 0.625 and 20 ng/ml for both I and II in serum. Overall the method developed was highly sensitive and could be employed for a wide range of studies.     

Vascular Dysfunction in Obstructive Sleep Apnea and Type 2 Diabetes Mellitus

Despite the high prevalence of obstructive sleep apnea (OSA) in type 2 diabetes mellitus (DM), the attributable vascular risk from each condition is unknown. We hypothesize that OSA may have a similar effect on vascular function as type 2 diabetes does. Healthy normal‐weight subjects, healthy obese subjects, subjects with type 2 diabetes, and obese subjects with OSA were enrolled. Vascular function was assessed with brachial artery ultrasound for flow‐mediated dilatation (FMD) and in skin microcirculation by laser Doppler flowmetry. One hundred fifty‐three subjects were studied: healthy normal‐weight controls (NCs) (n = 14), healthy obese controls (OCs) (n = 33), subjects with DM (n = 68), and obese subjects with OSA (n = 38). The DM group did not undergo sleep study and thus may have had subclinical OSA. The OSA and type 2 diabetes groups had impaired FMD as compared to both the normal‐weight and OC groups (5.8 ± 3.8%, 5.4 ± 1.6% vs. 9.1 ± 2.5%, 8.3 ± 5.1%, respectively, P < 0.001, post hoc Fischer test). When referenced to the NC group, a multiple linear regression model adjusting for covariates found that baseline brachial artery diameter (β = ?3.75, P < 0.001), OSA (β = ?2.45, P = 0.02) and type 2 diabetes status (β = ?2.31, P = 0.02), negatively predicted % FMD. OSA status did not seem to affect nitroglycerin‐induced vasodilation (endothelium‐independent) of the brachial artery or vascular function in the skin microcirculation. OSA impairs endothelial function in the brachial artery to a similar degree as type 2 diabetes does. OSA, however, does not appear to affect brachial endothelium‐independent vasodilation or skin microcirculatory function. Treatment of OSA in patients with concomitant type 2 diabetes, therefore, may be a potential therapeutic option to improve macro‐, but not microvascular outcomes.