Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo.

Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs.

Non-sedating benzodiazepines cause paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni.

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs.

Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability.

Recent reports indicate that α6β2/3γ2 GABAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAR α6 subtype was retained.

Design and synthesis of novel antimicrobials with activity against Gram-positive bacteria and mycobacterial species, including M. tuberculosis.

The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year.

Base-mediated stereospecific synthesis of aryloxy and amino substituted ethyl acrylates.

The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with phenols and N-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates.

A new class of potential anti-tuberculosis agents: Synthesis and preliminary evaluation of novel acrylic acid ethyl ester derivatives.

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents.

Facile synthesis of active antitubercular, cytotoxic and antibacterial agents: a Michael addition approach.

Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitubercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial profile.