A non-hormonal reversible contraceptive targeting GSK3α, a protein kinase, essential for epididymal sperm maturation.

Background And Objectives: Epididymal transit renders key competence to mammalian spermatozoa for fertilizing eggs. Generally, the two paralogs of glycogen synthase kinase 3, GSK3α and GSK3β, functionally overlap except in testis and sperm. We showed that GSK3α is essential for epididymal sperm maturation and fertilization.

A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells.

Survivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature.

Natural product-inspired aryl isonitriles as a new class of antimalarial compounds against drug-resistant parasites.

Malaria is a prevalent and deadly disease. The fast emergence of drug-resistant malaria parasites makes the situation even worse. Thus, developing new chemical entities, preferably with novel mechanisms of action, is urgent and important.

Classics in Chemical Neuroscience: U-47700.

U-47700, 3,4-dichloro--((1,2)-2-(dimethylamino)cyclohexyl)--methyl benzamide, is a novel synthetic opioid (NSO), discovered by the Upjohn company in the late 1970s. With potent activity, ∼10-times greater than that of morphine, U-47700 has become a drug of widespread abuse due to its ease of synthesis and, until recently, lack of robust detection methods by law enforcement. U-47700 has been found in counterfeit oxycodone tablets and is a key ingredient in "gray death.

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation.

Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its "undruggable" nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization.

An aryl isonitrile compound with an improved physicochemical profile that is effective in two mouse models of multidrug-resistant Staphylococcus aureus infection.

Objectives: The aim of this study was to investigate the antibacterial activity of a synthetic aryl isonitrile compound (35) that was developed as part of a compound library to identify new antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA).

Methods: Compound 35 was evaluated against MRSA isolates by the broth microdilution assay and for toxicity to mammalian keratinocytes using the MTS assay. A multistep resistance selection assay was conducted to investigate MRSA resistance development to 35.

Second-generation aryl isonitrile compounds targeting multidrug-resistant Staphylococcus aureus.

Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 to 4 µM) and were safe to human keratinocytes.

Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity.

Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge.

Discovery and characterization of aryl isonitriles as a new class of compounds versus methicillin- and vancomycin-resistant Staphylococcus aureus.

Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) have emerged as a global health concern. A new class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically-relevant MRSA and VRSA isolates. Structure-activity relationship studies have been conducted to identify the aryl isonitrile group as the key functional group responsible for the observed antibacterial activity.