STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.

Purpose: Commonly occurring oncogenic mutations in EGFR render non-small cell lung cancers sensitive to approved EGFR-targeted drugs. EGFR in-frame exon 20 insertion (ex20ins) mutants are, however, less sensitive to such drugs. The efficacy of existing medicines may in part be limited by their selectivity for ex20ins mutations relative to wild-type EGFR, which is important for epithelial tissue homeostasis.

Examining Kinetics and Product Inhibition in the Catalytic Intramolecular Schmidt Reaction.

In the intramolecular Schmidt reaction of alkyl azides and ketones, stoichiometric acid loading has often been necessary to overcome product inhibition, where the product amide irreversibly binds to the acid and forms a catalytically inactive complex. This limitation has been circumvented by the use of catalytic TiCl or AcCl in HFIP. Despite this advance, several issues and details of product inhibition in the intramolecular Schmidt reaction remain unexplored.

HFIP in Organic Synthesis.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C-H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

Tunable Heteroaromatic Sulfones Enhance in-Cell Cysteine Profiling.

Heteroaromatic sulfones react with cysteine via nucleophilic aromatic substitution, providing a mechanistically selective and irreversible scaffold for cysteine conjugation. Here we evaluate a library of heteroaromatic sulfides with different oxidation states, heteroatom substitutions, and a series of electron-donating and electron-withdrawing substituents. Select substitutions profoundly influence reactivity and stability compared to conventional cysteine conjugation reagents, increasing the reaction rate by >3 orders of magnitude.

An Interrupted Schmidt Reaction: C-C Bond Formation Arising from Nitrilium Ion Capture.

The rerouting of the nitrilium ion formed in the Schmidt reaction of ketones and TMSN to encompass C-C bond formation with an electron-rich aromatic group is reported. Thus, when the reaction is carried out in HFIP using AlCl or AlBr as the promoter, imines, iminium ions, or enamide derivatives are obtained through one-pot procedures. The scope and possible mechanisms of these new transformations are considered.

Chemoselective ratiometric imaging of protein S-sulfenylation.

Here we report a ratiometric fluorescent probe for chemoselective conjugation to sulfenic acids in living cells. Our approach couples an α-fluoro-substituted dimedone to an aminonaphthalene fluorophore (F-DiNap), which upon sulfenic acid conjugation is locked as the 1,3-diketone, changing the fluorophore excitation. F-DiNap reacts with S-sulfenylated proteins at equivalent rates to current probes, but the α-fluorine substitution blocks side-reactions with biological aldehydes.

Natural Withanolides in the Treatment of Chronic Diseases.

Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types.

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors.

Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention.

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol.

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN3 is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products.

Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol.

The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up.

Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues.

The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound.

Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction.

A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases.

Minor withanolides of Physalis longifolia: structure and cytotoxicity.

In our recent publication on bioactive guided isolation of compounds from Physalis longifolia (Solanaceae) novel anti-proliferative agents withalongolides A (4) and B (5), and their highly cytotoxic analogues, withalongolide A 4,19,27-triacetate (4a) and withalongolide B 4,19-diacetate (5a) were elucidated. In this study, the two lead compounds (4, 5) were re-isolated in gram quantities for the purpose of further analogue preparation and in vivo testing that would continue to probe structure-activity relationships. During this process, two additional withanolides, named withalongolides O (1) and P (2), were elucidated.

Copper-catalyzed oxaziridine-mediated oxidation of C-H bonds.

The highly regio- and chemoselective oxidation of activated C-H bonds has been observed via copper-catalyzed reactions of oxaziridines. The oxidation proceeded with a variety of substrates, primarily comprising allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C-H bond. The mechanism of the reaction is proposed to involve single-electron transfer to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final single-electron transfer event.

Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors.

The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors.

Progress in COX-2 inhibitors: a journey so far.

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity.

Acute administration of GPR40 receptor agonist potentiates glucose-stimulated insulin secretion in vivo in the rat.

Recently, several in vitro studies have shown that GPR40 receptor activation by free fatty acids (FFAs) results in glucose-dependent insulin secretion. However, whether GPR40 receptor activation results in glucose-dependent insulin secretion in vivo in rats is not known. Therefore, we evaluated the effect of synthetic GPR40 receptor agonist (compound 1) on glucose tolerance test (GTT) in fed, fasted, and insulin-resistant rats.