An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold.

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.

Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors.

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Surface Characteristics, Biodegradability and Biocompatibility of Porous Silicon for Microfabricated Neural Electrode.

Porous Si (PSi) used for microfabrication of a novel neural electrode was prepared on Si wafers by an anodization process. Surface morphology and porous structure of the PSi were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). 3D inter-connected and nano sized pores were homogeneously formed across the surface. Wettability of the PSi was determined using a sessile drop method. Although Si-Hx functional groups on the PSi surface had negative effect on wettability, water contact angle of the PSi reduced to 34.5 ± 0.5° due to the enhanced surface roughness and the capillary force generated by nano sized pores. Moreover, in vitro biocompatibility of the PSi was assessed by seeding a breast cancer cell line (MCF-7). After 5 days of culture, cell morphology was observed using a fluorescence microscope. Although more than 99% of the cells under the microscope were living for both Si and PSi samples, morphology of the cells attached on their surfaces was different. MTT assay was also used to quantitatively evaluate in vitro biocompatibility, and revealed false positive results due to the spontaneous reduction of MTT on the PSi surface. Therefore, MTT assay was not suitable for in vitro quantitatively study of PSi.

Telescoping intestine in an adult.

Protrusion of a bowel segment into another (intussusception) produces severe abdominal pain and culminates in intestinal obstruction. In adults, intestinal obstruction due to intussusception is relatively rare phenomenon, as it accounts for minority of intestinal obstructions in this population demographic. Organic lesion is usually identifiable as the cause of adult intussusceptions, neoplasms account for the majority. Therefore, surgical resection without reduction is almost always necessary and is advocated as the best treatment of adult intussusception. Here, we describe a rare case of a 44-year-old male with a diffuse large B-cell lymphoma involving the terminal ileum, which had caused ileocolic intussusception and subsequently developed intestinal obstruction requiring surgical intervention. This case emphasizes the importance of recognizing intussusception as the initial presentation for bowel malignancy.

Characterization of polymerized liposomes using a combination of dc and cyclical electrical field-flow fractionation.

Characterization of polymerized liposomes (PolyPIPosomes) was carried out using a combination of normal dc electrical field-flow fractionation and cyclical electrical field-flow fractionation (CyElFFF) as an analytical technique. The constant nature of the carrier fluid and channel configuration for this technique eliminates many variables associated with multidimensional analysis. CyElFFF uses an oscillating field to induce separation and is performed in the same channel as standard dc electrical field-flow fractionation separation. Theory and experimental methods to characterize nanoparticles in terms of their sizes and electrophoretic mobilities are discussed in this paper. Polystyrene nanoparticles are used for system calibration and characterization of the separation performance, whereas polymerized liposomes are used to demonstrate the applicability of the system to biomedical samples. This paper is also the first to report separation and a higher effective field when CyElFFF is operated at very low applied voltages. The technique is shown to have the ability to quantify both particle size and electrophoretic mobility distributions for colloidal polystyrene nanoparticles and PolyPIPosomes.

Diffusion Split-Flow Thin Cell (SPLITT) system for protein separations.

A diffusion Split-Flow Thin Cell (SPLITT) system was used to partially remove small peptides such as ß2 microglobulin (ß2M) and parathyroid hormone (PTH) in a continuous manner from an input flow stream while preserving most (over 97%) of the larger protein in the sample, such as albumin. To help determine the operating conditions for this work, a two-dimensional numerical model based on the Navier-Stokes equation and convection-diffusion equations was developed for diffusional SPLITT using COMSOL multiphysics software (COMSOL Inc., MA). These simulations were used to obtain the relationship between important operational parameters and the purification efficiency for proteins of interest. The diffusion-based SPLITT system was fabricated using xurography and was used to demonstrate protein purification based on the differences in size or diffusion coefficient of the sample. The results obtained from the experiments are compared with the mathematical model and show good agreement, while the variations between these results are discussed. The results show that significant portions of small peptides (>25%) can be removed while preserving larger proteins (up to 95%) in the carrier stream. A potential application of this technique is to be used as an additional step in kidney dialysis to remove toxins that are not effectively removed by current dialysis protocols.

Vitamin D status before Roux-en-Y and efficacy of prophylactic and therapeutic doses of vitamin D in patients after Roux-en-Y gastric bypass surgery.

BACKGROUND: Literature regarding the effect of Roux-en-Y gastric bypass (RYGBP) on vitamin D level shows contradictory findings. Our goal was to determine preoperatively vitamin D levels, to evaluate the efficacy of therapeutic and prophylactic doses of vitamin D and to assess the relationship of 25-OH vitamin D level and body mass index (BMI). METHODS: We conducted a retrospective cross-sectional study of 72 patients who underwent RYGBP from April 2007 to October 2007 in Bariatric Surgery Department at Saint Vincent Charity Hospital. RESULTS: Our study demonstrated that 80% of the obese patients undergoing RYGBP had serum 25-OH vitamin D levels of less than 32 ng/ml. Postoperative data show that 45% of these patients continue being vitamin D insufficient despite the treatment. We demonstrated that a statistically significant inverse correlation between BMI and 25-OH vitamin D levels (r = 0.464, p = 0.01) exists. CONCLUSION: Our finding strongly supports the need for aggressive monitoring of vitamin D levels for long-term prevention of complications of vitamin D deficiency in gastric bypass patients. Identifying the factors that predict patient's responses to vitamin D supplementation requires larger-scale studies and further analysis of these tendencies suggested by our findings.

Identification of essential amino acid changes in paired domain evolution using a novel combination of evolutionary analysis and in vitro and in vivo studies.

Pax genes are defined by the presence of a paired box that encodes a DNA-binding domain of 128 amino acids. They are involved in the development of the central nervous system, organogenesis, and oncogenesis. The known Pax genes are divided into five groups within two supergroups. By means of a novel combination of evolutionary analysis, in vitro binding assays and in vivo functional analyses, we have identified the key residues that determine the differing DNA-binding properties of the two supergroups and of the Pax-2, 5, 8 and Pax-6 subgroups within supergroup I. The differences in binding properties between the two supergroups are largely caused by amino acid changes at residues 20 and 121 of the paired domain. Although the paired domains of the Pax-2, 5, 8 and the Pax-6 group differ by >19 amino acids, their distinct DNA-binding properties are determined almost completely by a single amino acid change. Thus, a small number of amino acid changes can account in large part for the divergence in binding properties among the known paired domains. Our approach for selecting candidate sites responsible for the functional divergence between genes should also be useful for studying other gene families.