Palladium-Catalyzed Synthesis of Alkynes via a Tandem Decarboxylation/Elimination of (<i>E</i>)‑Enol Triflates

A mild catalytic synthesis of alkynes via a tandem Pd-catalyzed decarboxylation/elimination of enol triflates is described. Key attributes of the method include readily available starting materials, broad functional group tolerance, and the ability to access terminal, internal, and halogenated alkynes. The preliminary scope of the reaction is demonstrated on 25 different examples with yields ranging from 63% to 96%

Pd-Catalyzed Asymmetric β‑Hydride Elimination en Route to Chiral Allenes

We wish to report our preliminary results on the discovery and development of a catalytic, asymmetric β-hydride elimination from vinyl Pd­(II)-complexes derived from enol triflates to access chiral allenes. To achieve this, we developed a class of chiral phosphite ligands that demonstrate high enantioselectivity, allow access of either allene enantiomer, and are readily synthesized. The methodology is demonstrated on over 20 substrates, and application to the formal asymmetric total synthesis of the natural product, (+)-epibatidine, is also provided

Unified Approach to Substituted Allenoates via Pd-Catalyzed β‑Hydride Elimination of (<i>E</i>)‑Enol Triflates

A robust synthesis of allenoates via a Pd-catalyzed β-hydride elimination of (<i>E</i>)-enol triflates is presented. Salient features of this method include low catalyst loadings, mild reaction conditions, and the ability to access all four patterns of substituted allenoates from a single substrate class

Development of an Ex Vivo Lymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50) &gt; 100; 19 of the compounds had an EC50 below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis

Targeting Native Adult Heart Progenitors with Cardiogenic Small Molecules

Targeting native progenitors with small molecule pharmaceuticals that direct cell fate decisions is an attractive approach for regenerative medicine. Here, we show that 3,5-disubstituted isoxazoles (Isx), stem cell-modulator small molecules originally recovered in a P19 embryonal carcinoma cell-based screen, directed cardiac muscle gene expression <i>in vivo</i> in target tissues of adult transgenic reporter mice. Isx also stimulated adult mouse myocardial cell cycle activity. Narrowing our focus onto one target cardiac-resident progenitor population, Isx directed muscle transcriptional programs <i>in vivo</i> in multipotent Notch-activated epicardium-derived cells (NECs), generating Notch-activated adult cardiomyocyte-like precursors. Myocardial infarction (MI) preemptively differentiated NECs toward fibroblast lineages, overriding Isx’s cardiogenic influence in this cell population. Isx dysregulated gene expression <i>in vivo</i> in Notch-activated repair fibroblasts, driving distinctive (pro-angiogenesis) gene programs, but failed to mitigate fibrosis or avert ventricular functional decline after MI. In NECs <i>in vitro</i>, Isx directed partial muscle differentiation, which included biosynthesis and assembly of sarcomeric α-actinin premyofibrils, beaded structures pathognomonic of early developing cardiomyocytes. Thus, although Isx small molecules have promising <i>in vivo</i> efficacy at the level of cardiac muscle gene expression in native multipotent progenitors and are first in class in this regard, a greater understanding of the dynamic interplay between fibrosis and cardiogenic small molecule signals will be required to pharmacologically enable regenerative repair of the heart