Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Green Methodologies for Copper(I)-Catalyzed Azide-Alkyne Cycloadditions: A Comparative Study.

Successful copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions may be achieved by several methods. In this paper, four synthetic protocols were performed for direct comparison of time required for the synthesis, yield, and purity of the 1H-1,2,3-triazole products. The methods with Cu(I) catalysts were conventional, microwave heating, solvent-free, and a method using glycerol solvent. The compounds synthesized in this paper were known non-fluorinated triazoles and new fluorinated triazoles. The results lead to the conclusion that the microwave method should be strongly considered for CuAAC syntheses.

Exploring the combinatorial explosion of amine-acid reaction space via graph editing.

Amines and carboxylic acids are abundant chemical feedstocks that are nearly exclusively united via the amide coupling reaction. The disproportionate use of the amide coupling leaves a large section of unexplored reaction space between amines and acids: two of the most common chemical building blocks. Herein we conduct a thorough exploration of amine-acid reaction space via systematic enumeration of reactions involving a simple amine-carboxylic acid pair. This approach to chemical space exploration investigates the coarse and fine modulation of physicochemical properties and molecular shapes. With the invention of reaction methods becoming increasingly automated and bringing conceptual reactions into reality, our map provides an entirely new axis of chemical space exploration for rational property design.

Coronary Vasospasm Associated With Synthetic Marijuana Resulting in Transient Electrocardiogram Changes and Troponin Elevation.

Chest pain is a common presentation in the emergency department requiring prompt evaluation and risk stratification to assess for acute coronary syndrome versus non-cardiac causes. In the past, cocaine has been documented to be associated with the presentation of acute myocardial infarction. This case report describes a rare case of coronary vasospasm with transient electrocardiogram (EKG) changes and significantly elevated troponin in an individual presenting with a recent history of synthetic marijuana use. This report highlights the initial presentation, progression, and management of synthetic marijuana-associated coronary vasospasm mimicking the presentation of acute myocardial infarction. This is a unique case that describes not only the clinical presentation with dynamic EKG changes but also significantly elevated biomarkers, as would be seen with acute myocardial infarction. Challenges associated with synthetic marijuana-mediated coronary vasospasm are not only related to the management but also present a diagnostic challenge because it is not easily detected by urinary drug screen compared to traditional marijuana.