Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote ().

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent.

Label-free discrimination and quantitative analysis of oxidative stress induced cytotoxicity and potential protection of antioxidants using Raman micro-spectroscopy and machine learning.

Diesel exhaust particles (DEPs) are major constituents of air pollution and associated with numerous oxidative stress-induced human diseases. In vitro toxicity studies are useful for developing a better understanding of species-specific in vivo conditions. Conventional in vitro assessments based on oxidative biomarkers are destructive and inefficient.

Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins.

Amphiphilic kanamycins bearing hydrophobic modifications at the 6″ position have attracted interest due to remarkable antibacterial-to-antifungal switches in bioactivity. In this report, we investigate a hurdle that hinders practical applications of these amphiphilic kanamycins: a cost-effective synthesis that allows the incorporation of various connecting functionalities to which the hydrophobic moieties are connected to the kanamycin core. A cost-effective tosylation enables various modifications at the 6″ position, which is scalable to a 90-g scale.

Cationic Anthraquinone Analogs as Selective Antimicrobials.

Development of new antibiotics is always needed in the fight against growing threat from multiple drug-resistant bacteria, such as resistant Gram-negative (G-) and . While the development of broad-spectrum antibiotics has attracted great attention, careful administration of these antibiotics is important to avoid adverse effects, like infection (CDI). The use of broad-spectrum antibiotics, for example, quinolones, can increase the risk of CDI by eradicating the protective bacteria in intestine and encouraging spore germination.

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation.

Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components.

Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus.

Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed.

Antifungal amphiphilic kanamycins: new life for an old drug.

Classical aminoglycoside antibiotics are obsolete or hampered by the emergence of drug resistant bacteria. Recent discoveries of antifungal amphiphilic kanamycins offer new strategies for reviving and repurposing these old drugs. A simple structural modification turns the clinically obsolete antibacterial kanamycin into an antifungal agent.

Synthesis and biological activity investigation of azole and quinone hybridized phosphonates.

Phosphonates, azoles and quinones are pharmacophores found in bioactive compounds. A series of phosphonates conjugated to azoles and quinones with variable carbon chain lengths were synthesized in 3-4 steps with good yield. Antifungal assay of these compounds showed that ethyl protected phosphates have excellent inhibitory activity against phytopathogenic fungus Fusarium graminearum, and the free-base phosphates have good activity against human pathogenic fungi Aspergillus flavus and Candida albicans.

One-step synthesis of carbohydrate esters as antibacterial and antifungal agents.

Carbohydrate esters are biodegradable, and the degraded adducts are naturally occurring carbohydrates and fatty acids which are environmentally friendly and non-toxic to human. A simple one-step regioselective acylation of mono-carbohydrates has been developed that leads to the synthesis of a wide range of carbohydrate esters. Screening of these acylated carbohydrates revealed that several compounds were active against a panel of bacteria and fungi, including Staphylococcus aureus, methicillin-resistant S.

Aminoglycoside interactions and impacts on the eukaryotic ribosome.

Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored.

Synthesis and bioactivity investigation of quinone-based dimeric cationic triazolium amphiphiles selective against resistant fungal and bacterial pathogens.

A series of synthetic dimeric cationic anthraquinone analogs (CAAs) with potent antimicrobial activities against a broad range of fungi and bacteria were developed. These compounds were prepared in 2-3 steps with high overall yield and possess alkyl chain, azole, quinone, and quaternary ammonium complexes (QACs). In vitro biological evaluations reveal prominent inhibitory activities of lead compounds against several drug-susceptible and drug-resistant fungal and bacterial strains, including MRSA, VRE, Candida albicans and Aspergillus flavus.

Divergent Synthesis of Three Classes of Antifungal Amphiphilic Kanamycin Derivatives.

A concise and novel method for site-selective alkylation of 1,3,6',3″-tetraazidokanamycin has been developed that leads to the divergent synthesis of three classes of kanamycin A derivatives. These new amphiphilic kanamycin derivatives bearing alkyl chains length of 4, 6, 7, 8, 9, 10, 12, 14, and 16 have been tested for their antibacterial and antifungal activities. The antibacterial effect of the synthesized kanamycin derivatives declines or disappears as compared to the original kanamycin A.

Structure-activity relationships for antibacterial to antifungal conversion of kanamycin to amphiphilic analogues.

Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4″ position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3″-NH2 group of kanamycin B was synthesized.

Three new fusidic acid derivatives and their antibacterial activity.

Two steroid acids, cephalosporin P1 and isocephalosporin P1, were isolated from Hapsidospora irregularis FERM BP-2511. These compounds are structurally related to fusidic acid. Their NMR data were completely assigned on the basis of the 2D NMR spectra.

Cyclopamine: from cyclops lambs to cancer treatment.

In the late 1960s, the steroidal alkaloid cyclopamine was isolated from the plant Veratrum californicum and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western United States. Cyclopamine was found to inhibit the hedgehog (Hh) signaling pathway, which plays a critical role in embryonic development. More recently, aberrant Hh signaling has been implicated in several types of cancer.

Synthesis and anticancer structure activity relationship investigation of cationic anthraquinone analogs.

We have synthesized a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium salts, which can be viewed as analogs of cationic anthraquinones. Unlike the similar analogs that we have reported previously, these compounds show relatively weak antibacterial activities but exert strong anticancer activities (low μM to nM GI50), in particular, against melanoma, colon cancer, non-small cell lung cancer and central nervous system (CNS) cancer. These compounds are structurally different from their predecessors by having the aromatic group, instead of alkyl chains, directly attached to the cationic anthraquinone scaffold.

Safe and easy route for the synthesis of 1,3-dimethyl-1,2,3-triazolium salt and investigation of its anticancer activities.

We have developed a new safe and easy route for the synthesis of 1,3-dimethyl-1,2,3-triazolium derivatives. We have reported the synthesis of 4,9-dioxo-1,3-dimethylnaphtho[2,3-d][1,2,3]triazol-3-ium chloride from methylation of 1-methyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione. The synthesis of 1-methyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione is inefficient as a significant amount of by-product is formed that is difficult to separate and also unsafe as it requires the use of hazardous methylazide as a starting material.

Mesobiliverdin IXα Enhances Rat Pancreatic Islet Yield and Function.

The aims of this study were to produce mesobiliverdin IXα, an analog of anti-inflammatory biliverdin IXα, and to test its ability to enhance rat pancreatic islet yield for allograft transplantation into diabetic recipients. Mesobiliverdin IXα was synthesized from phycocyanobilin derived from cyanobacteria, and its identity and purity were analyzed by chromatographic and spectroscopic methods. Mesobiliverdin IXα was a substrate for human NADPH biliverdin reductase.

Stereoselective potencies and relative toxicities of γ-coniceine and N-methylconiine enantiomers.

γ-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized γ-coniceine and the enantiomers of N-methylconiine and determined the biological activity of γ-coniceine and each of the N-methylconiine enantiomers in vitro and in vivo.

Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and caused by the loss of functional Survival Motor Neuron 1 (SMN1). The remaining copy gene, SMN2, is unable to rescue from disease because the primary gene product lacks the final coding exon, exon 7, due to an alternative splicing event. While SMNΔ7 is a rapidly degraded protein, exon 7 is not specifically required in a sequence-specific manner to confer increased functionality to this truncated protein.

Development of a monoclonal antibody-based ELISA for the hedgehog inhibitors cyclopamine and KAAD-cyclopamine.

Cyclopamine (1) was isolated from the plant Veratrum californicum Durand (Liliacea) and identified as the teratogen responsible for severe craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in central Idaho. More recently, cyclopamine (1) was found to inhibit the hedgehog (Hh) signaling pathway which plays a critical role in embryonic development and is implicated in several types of cancer. Thus, cyclopamine (1) and cyclopamine derivatives have been targeted as potential pharmaceutical treatments for certain cancers and other diseases associated with the Hh signaling pathway.

Library synthesis and antibacterial investigation of cationic anthraquinone analogs.

We report the parallel synthesis of a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium chloride salts, which are analogs to cationic anthraquinones. Three synthetic protocols were examined leading to a convenient and facile library synthesis of the cationic anthraquinone analogs that contain double alkyl chains of various lengths (C(2)-C(12)) at N-1 and N-3 positions. The antibacterial activities of these compounds were evaluated against Gram-positive bacterium Staphylococcus aureus and Gram-negative bacterium Escherichia coli.

Mode of action investigation for the antibacterial cationic anthraquinone analogs.

Reported previously by our group, we have developed a novel class of antibacterial cationic anthraquinone analogs with superb potency (MIC <1μg/mL) against Gram positive (G+) pathogens including Methicillin-resistant Staphylococcus aureus (MRSA). However, most of these compounds only manifest modest antibacterial activity against Gram negative (G-) bacteria. Further investigation on the antibacterial mode of action using fluorogenic dyes reveals that these compounds exert two different modes of action that account for the difference in their antibacterial profile.