Methionine aminopeptidases: Potential therapeutic target for microsporidia and other microbes.

Methionine aminopeptidases (MetAPs) have emerged as a target for medicinal chemists in the quest for novel therapeutic agents for treating cancer, obesity, and other disorders. Methionine aminopeptidase is a metalloenzyme with two structurally distinct forms in humans, MetAP-1 and MetAP-2. The MetAP2 inhibitor fumagillin, which was used as an amebicide in the 1950s, has been used for the successful treatment of microsporidiosis in humans; however, it is no longer commercially available. Despite significant efforts and investments by many pharmaceutical companies, no new MetAP inhibitors have been approved for the clinic. Several lead compounds have been designed and synthesized by researchers as potential inhibitors of MetAP and evaluated for their potential activity in a wide range of diseases. MetAP inhibitors such as fumagillin, TNP-470, beloranib, and reversible inhibitors and their analogs guide new prospects for MetAP inhibitor development in the ongoing quest for new pharmacological indications. This perspective provides insights into recent advances related to MetAP, as a potential therapeutic target in drug discovery, bioactive small molecule MetAP2 inhibitors, and data on the role of MetAP-2 as a therapeutic target for microsporidiosis.

Decline in unmet needs for cataract surgery among the ageing population in India: findings from LASI, wave-1.

Introduction: Cataracts are the leading cause of blindness among older people, but they can be treated with corrective surgery. India boasts the oldest blindness control programme in the world. We aimed to assess the prevalence of cataract surgery, and we compared the determinants of undergoing cataract surgery and identified the unmet needs for cataract surgery among older adults in India. Methods: We included 52,380 individuals aged ≥50 years from the Longitudinal Ageing Study in India, wave-1. The primary outcome measures of our study were the prevalence of cataract surgery and the unmet need for cataract surgery. Multivariate analysis was executed to investigate the association between socio-demographic variables and outcomes, expressing the results as adjusted odds ratios with 95% confidence intervals (CIs). Results: The overall prevalence of cataracts was 14.85%. The coverage of cataract surgery was 76.95%, with 23% having unmet needs for cataract surgery. Notably, cataract surgery coverage was higher at 78.30% (95% CI: 76.88-79.48) among participants aged 66-80 years, while the percentage of those who did not undergo cataract surgery was higher at 24.62% (95% CI: 23.09-26.20) among participants aged 50-60 years. The most deprived group had a higher odds ratio [adjusted odds ratio: 1.20 (95% CI: 1.00-1.44)] (p < 0.05) of having unmet needs for cataract surgery. Conclusions: There is a considerable burden of age-related cataracts in India. While the coverage of cataract surgery is high, the unmet need for cataract surgery cannot be overlooked. The existing blindness control programme has contributed significantly to increasing the coverage of cataract surgery, but it still needs to be strengthened, especially to reach the most deprived sections of society.

Identification of new hit to lead magmas inhibitors as potential therapeutics for glioblastoma.

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.

Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease.

The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death.

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure-activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer's agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.

To Study the Efficacy of Laser Peripheral Iridoplasty in the Treatment of Eyes With Primary Angle Closure and Plateau Iris Syndrome, Unresponsive to Laser Peripheral Iridotomy, Using Anterior-Segment OCT as a Tool.

PURPOSE: To use anterior-segment optical coherence tomography (AS-OCT) as a tool to monitor the outcome of iridoplasty in patients with primary angle closure (PAC) and plateau iris syndrome (PIS), who were unresponsive to a previous laser peripheral iridotomy. MATERIALS AND METHODS: This was a prospective, observational case control study. Patients diagnosed with PAC and PIS who had undergone laser peripheral iridotomy earlier, but were unresponsive to the procedure, were subjected to an iridoplasty. The intraocular pressure (IOP) and anterior-chamber parameters were measured before and after the procedure, and complications were noted. The patients were followed up for 1 year, and results were analyzed. RESULTS: Twenty-four eyes of 12 patients underwent the iridoplasty procedure. Sixteen eyes were diagnosed as cases of PAC and 8 eyes were diagnosed as cases of PIS. Main outcome measures were the IOP, peripheral anterior synechiae, AS-OCT angle parameters, and complications. After iridoplasty, there was a significant decrease in the IOP from 24.4±5.6 to 16.5±5.4 mm Hg (P<0.001) at the final follow-up. The mean number of antiglaucoma medications decreased from 1.6±0.9 to 0.7±1.1. The medians of the peripheral anterior synechiae extent reduced from 3.5 (quartile range, 1.5 to 6.0) to 2.0 (quartile range, 0.5 to 4.0) clock hours in the PAC group (P<0.001) and from 3.8 (quartile range, 2.0 to 6.5) to 2.5 (quartile range, 0.8 to 5.0) clock hours in the PIS group (P<0.001). Changes in AS-OCT parameters noted were as follows: the AOD500 increased from 0.132±0.016 to 0.179±0.062 mm (P<0.001), TISA500 from 0.085±0.012 to 0.104±0.051 mm (P<0.001), and scleral spur angle from 19.5±2.4 to 26.8±4.5 degrees (P<0.001). No significant changes in the angle-to-angle distance and the crystalline lens rise were found. CONCLUSIONS: In eyes with synechial angle closure and PIS that do not show an improvement after an iridotomy, laser peripheral iridoplasty can be very effective. There were no significant complications after the iridoplasty procedure, implying that it is quite safe. This study also demonstrates that AS-OCT can serve as a useful tool to document the preprocedure angle parameters, to note the changes after the procedure, and for the long-term follow-up of these patients.

Retinoic acid signaling pathways in development and diseases.

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.

Boron chemicals in diagnosis and therapeutics.

Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade(®)), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin's lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans.

Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.

In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.

5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.

A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.

A novel technique of selective uterine devascularization before myomectomy at the time of cesarean section: a pilot study.

Selective uterine devascularization before myomectomy at the time of cesarean section is a novel technique that facilitates myomectomy and is a safe procedure avoiding the need for subsequent surgery.

9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation.

A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia.

Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors.

Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.