Gastrointestinal Manifestations of Immunodeficiency: Imaging Spectrum.

There is a wide spectrum of hereditary and acquired immunodeficiency disorders that are characterized by specific abnormalities involving a plethora of humoral, cellular, and phagocytic immunologic pathways. These include distinctive primary immunodeficiency syndromes due to characteristic genetic defects and secondary immunodeficiency syndromes, such as AIDS from HIV infection and therapy-related immunosuppression in patients with cancers or a solid organ or stem cell transplant. The gut mucosa and gut-associated lymphoid tissue (the largest lymphoid organ in the body), along with diverse commensal microbiota, play complex and critical roles in development and modulation of the immune system.

Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors.

Herein we describe the design, synthesis and anticancer evaluation of a series of 2,3-dihydroimidazo[2,1-b]thiazoles as dual kinase inhibitors of IGF1R and EGFR. A series of saturated dihydroimidazo[2,1-b] thiazoles were synthesized to understand the structure-activity relationship. Further, the key modifications were performed to improve drug like properties of the series.

Synthesis of Substituted imidazo [1, 5-a] pyrimidine-2-(1H)-one Core Structure.

Background And Objective: The objective of our work was to establish a facile and scalable synthesis of imidazopyridone for further use in medicinal chemistry applications. An easy synthesis of a core scaffold will enable the medicinal chemistry community to use imidazopyridone as a privileged scaffold in new chemical entity (NCE) synthesis.

Materials And Methods: The synthesis was achieved from commercially available and cheap raw materials like amino acetonitrile hydrochloride or commercially available guanidine.

Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents.

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.

Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor.

A series of novel 2-amino-4-pyrazolecyclopentylpyrimidines have been prepared and evaluated as IGF-1R tyrosin kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 2- amino ring, 4-pyrazolo moieties and size of fused saturated ring with the central pyrimidine core. A stepwise optimization by combination of active fragments led to discovery of compound 6f and 6k, two structures with IGF-1R IC50 of 20 nM and 10 nM, respectively.

Effect of needle gauge and lobe laterality on parenchymal liver biopsy outcome: a retrospective analysis.

Purpose: To analyze the effect of lobe selection, needle gauge, and number of passes on procedure outcomes in terms of specimen length and post-procedure complications.

Methods: In this HIPAA-compliant, IRB-approved retrospective study, the data from 771 ultrasound-guided adult parenchymal liver biopsies were analyzed. Post-procedure complications were assigned a 3-point rating scale.

Dynamic contrast-enhanced MRI findings of acute pancreatitis in ectopic pancreatic tissue: case report and review of the literature.

Context: Acute pancreatitis in ectopic pancreatic tissue is an uncommon cause of acute abdominal pain and can be difficult to diagnose on imaging. Our aim is to raise awareness and aid in the diagnosis of this entity by highlighting helpful dynamic contrast-enhanced MRI imaging findings.

Case Report: We report a 51-year-old man with acute onset epigastric pain presented to ER.

Computerized 3-dimensional localization of a video capsule in the abdominal cavity: validation by digital radiography.

Background: Wireless video capsule endoscopy allows the noninvasive visualization of the small intestine. Currently, capsules do not provide localization information while traversing the GI tract.

Objective: To report on the radiological validation of 3-dimensional localization software incorporated in a newly developed capsule.

First total synthesis of prasinic acid and its anticancer activity.

The first total synthesis of prasinic acid is being reported along with its biological evaluation. The ten step synthesis involved readily available and cheap starting materials and can easily be transposed to large scale manufacturing. The crucial steps of the synthesis included the formation of two different aromatic units (7 and 9) and their coupling reaction.

Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics.

Modulation of cytochrome-P450 inhibition (CYP) in drug discovery: a medicinal chemistry perspective.

Cytochrome P450 (CYP450) has widely been implicated for drug-drug interactions (DDI) in the pharmaceutical industry. Inhibition or induction of this enzyme family has led to withdrawal of multiple drugs from the market leading to major time and financial losses for the pharmaceutical industry. CYP450 plays a prevailing role in the biotransformation of a large number of structurally diverse drugs.

5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile.

Novel substituted pyrimidines as HCV replication (replicase) inhibitors.

Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety.

Recent advances in the discovery of small molecule mTOR inhibitors.

Mammalian target of rapamycin (mTOR) belongs to the atypical kinase family of phosphatidylinositol-3-kinase-related kinase and function as a master regulators of the switch between catabolic and anabolic metabolism. In the last decade mTOR has emerged as a therapeutic target for various diseases such as cancer, inflammation and metabolic disorders. mTOR plays a crucial role in the PI3K/AKT/PDK1 pathway.

Synthesis and therapeutic evaluation of pyridyl based novel mTOR inhibitors.

A series of novel cyanopyridyl based molecules (1-14) were designed, synthesized and probed for inhibition of mammalian target of rapamycin (mTOR) activity. Compound 14 was found to be a potent inhibitor of mTOR activity as assessed by enzyme-linked immunoassays and Western blot analysis. Most importantly, systemic application (intraperitoneal; ip) of compound 14 significantly suppressed macroscopic and histological abnormalities associated with chemically-induced murine colitis.

Modification of the structure of peptidoglycan is a strategy to avoid detection by nucleotide-binding oligomerization domain protein 1.

Nucleotide-binding oligomerization domain (NOD) protein 1 (NOD1) and NOD2 are pathogen recognition receptors that sense breakdown products of peptidoglycan (PGN) (muropeptides). It is shown that a number of these muropeptides can induce tumor necrosis factor alpha (TNF-alpha) gene expression without significant TNF-alpha translation. This translation block is lifted when the muropeptides are coincubated with lipopolysaccharide (LPS), thereby accounting for an apparently synergistic effect of the muropeptides with LPS on TNF-alpha protein production.

Crystal structure of human peptidoglycan recognition protein I alpha bound to a muramyl pentapeptide from Gram-positive bacteria.

Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors of the innate immune system that bind bacterial peptidoglycans (PGNs). We determined the crystal structure, to 2.1 A resolution, of the C-terminal PGN-binding domain of human PGRP-I alpha in complex with a muramyl pentapeptide (MPP) from Gram-positive bacteria containing a complete peptide stem (L-Ala-D-isoGln-L-Lys-D-Ala-D-Ala).

Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs).

The innate immune system constitutes the first line of defense against microorganisms in both vertebrates and invertebrates. Although much progress has been made toward identifying key receptors and understanding their role in host defense, far less is known about how these receptors recognize microbial ligands. Such studies have been severely hampered by the need to purify ligands from microbial sources and a reliance on biological assays, rather than direct binding, to monitor recognition.

Synthesis and proinflammatory properties of muramyl tripeptides containing lysine and diaminopimelic acid moieties.

The unusual amino acid diaminopimelic acid (DAP) was prepared by cross metathesis of appropriately protected vinyl glycine and allyl glycine derivatives. Catalytic hydrogenation of the cross-coupling product resulted in reduction of the double bond and the removal of protecting groups. The resulting compounds were appropriately protected for the polymer-supported and solution-phase synthesis of muramyl tripeptides 2 and 3, which differ in the amidation of the alpha-carboxylic acids of the isoglutamine and DAP moieties.

Selective recognition of synthetic lysine and meso-diaminopimelic acid-type peptidoglycan fragments by human peptidoglycan recognition proteins I{alpha} and S.

The interactions of a range of synthetic peptidoglycan derivatives with PGRP-Ialpha and PGRP-S have been studied in real-time using surface plasmon resonance. A dissociation constant of K(D) = 62 mum was obtained for the interaction of peptidoglycan recognition protein (PGRP)-Ialpha with the lysine-containing muramyl pentapeptide (compound 6). The normalized data for the lysine-containing muramyl tetra- (compound 5) and pentapeptide (compound 6) showed that these compounds have similar affinities, whereas a much lower affinity for muramyl tripeptide (compound 3) was measured.

Structural basis for peptidoglycan binding by peptidoglycan recognition proteins.

Peptidoglycan (PGN) recognition proteins (PGRPs) are pattern-recognition receptors of the innate immune system that bind and, in some cases, hydrolyze bacterial PGNs. We determined the crystal structure, at 2.30-A resolution, of the C-terminal PGN-binding domain of human PGRP-Ialpha in complex with a muramyl tripeptide representing the core of lysine-type PGNs from Gram-positive bacteria.

2'-deoxycytidines carrying amino and thiol functionality: synthesis and incorporation by Vent (exo-) polymerase.

[reaction: see text] The synthesis of 2'-deoxycytidine nucleosides bearing amino and thiol groups appended to the 5-position of the nucleobase via a butynyl linker is described. The corresponding triphosphates were then synthesized from the nucleoside and incorporated into oligonucleotides by Vent (exo(-)) DNA polymerase. The ability of Vent (exo(-)) polymerase to amplify oligonucleotides containing these functionalized cytidine derivatives in a polymerase chain reaction (PCR) was demonstrated for the amino-functionalized derivative.

C-5 modified nucleosides: direct insertion of alkynyl-thio functionality in pyrimidines.

A route is presented to append, in a single step, alkynyl thioesters to the 5-position of a pyrimidine ring of a nucleoside that is unprotected. These products should be useful to support in vitro selection experiments with functionalized DNA.