Mild oxidation of tosylmethylisocyanide to tosylmethylisocyanate: utility in synthetic and medicinal chemistry.

A convenient and efficient (one-step) oxidation is reported of commercially available tosylmethylisocyanide (TOSMIC) to form tosylmethylisocyanate, making this highly reactive bifunctional molecule a readily available synthetic reagent. Besides engaging in nucleophilic addition reactions with alcohols, amines and thiols, tosylmethylisocyanate also reacts with carboxylic acids to form tosylmethylamides, which undergo substitution reactions in the presence of organocopper and organomagnesium reagents.

A Simple, General Synthesis of Carbonimidic Dichlorides.

The reaction of aliphatic and aromatic isonitriles with sulfuryl chloride provides an efficient, general route to the corresponding dichlorides without byproducts of free-radical substitution.

Studies on the synthesis of amidoximes from nitroalkanes.

The reaction of primary nitroalkanes with magnesium or lithium amides provides a convenient, one-step synthesis of substituted amidoximes.

Trifluoroacetic anhydride-catalyzed oxidation of isonitriles by DMSO: a rapid, convenient synthesis of isocyanates.

A smooth and efficient oxidation of isonitriles to isocyanates by sulfoxides is catalyzed by trifluoroacetic anhydride. With use of DMSO as the oxidant and 5 mol·% TFAA (dichloromethane, -60 to 0 °C), the process is complete in a few minutes, forming dimethyl sulfide as the only byproduct. The newly formed isocyanates may be used directly or isolated in high purity by solvent evaporation.

Use of multicomponent reactions in developing small-molecule tools to study GABAA receptor mechanism and function.

We discuss the potential use of multicomponent reactions in developing small-molecule probes of GABA(A) receptor function. Two examples that illustrate this approach are presented: the synthesis of a class of compounds that specifically modulate the function of GABA(A) receptors containing the δ-subunit, and also 'caged' GABA derivatives. A caged GABA is a photolabile precursor of GABA that releases GABA upon photolysis.

Dihydropyrimidinone positive modulation of delta-subunit-containing gamma-aminobutyric acid type A receptors, including an epilepsy-linked mutant variant.

Gamma-aminobutyric acid type A receptors (GABA(A) receptors) are ligand-gated chloride channels that play a central role in signal transmission within the mammalian central nervous system. Compounds that modulate specific GABA(A) receptor subtypes containing the delta-subunit are scarce but would be valuable research tools and starting points for potential therapeutic agents. Here we report a class of dihydropyrimidinone (DHPM) heterocycles that preferentially potentiate peak currents of recombinant GABA(A) receptor subtypes containing the delta-subunit expressed in HEK293T cells.

A new synthesis of caged GABA compounds for studying GABAA receptors.

A short and convergent synthetic approach to new photoactivatable precursors of gamma-aminobutyric acid (GABA) is described. When photolyzed, the 'caged' GABA precursor efficiently releases GABA, as judged by depolarization measurements on the mammalian GABA(A) receptor.

Strategies for innovation in multicomponent reaction design.

By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-19th century when Strecker first produced alpha-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs.

Studies on the chemistry and reactivity of alpha-substituted ketones in isonitrile-based multicomponent reactions.

Using the Passerini and Ugi reactions as representative tests, the utility of several alpha-substituted ketones R-CO-CH(2)-X (X = sulfonyloxy, acyloxy, azido, halo, hydroxy, and sulfonyl) in isonitrile-based multicomponent reactions was explored. In a relative rate study (R = PhCH(2)CH(2)), each of the alpha-substituted ketones underwent Passerini condensation more rapidly than the parent ketone. Short, highly convergent routes to oxazoline, beta-lactam, di-O-acylglyceramides, and other molecular frameworks were developed.

A three-component Fischer indole synthesis.

This protocol describes a three-component approach to multiply-substituted indoles from nitriles, organometallic reagents and arylhydrazine hydrochloride salts. The condensation of organolithium or Grignard reagents with nitriles produces metalloimines, which under acidic conditions and in the presence of arylhydrazines lead to arylhydrazones, the starting materials for the Fischer indole reaction. Combining this approach with the Fischer indole reaction produces indoles in an efficient, one-pot process.

One-pot synthesis of polysubstituted indoles from aliphatic nitro compounds under mild conditions.

Polysubstituted indoles can be prepared directly from functionalized nitroalkanes under very mildly acidic conditions in a simple, one-pot, two-stage procedure.

Bioactive 2-oxazolines: a new approach via one-pot, four-component reaction.

Substituted 2-oxazolines of the general structure shown above are found in several families of bioactive natural products and can be prepared in an efficient and general one-pot, four-component condensation.

Paclitaxel from primary taxanes: a perspective on creative invention in organozirconium chemistry.

In this Perspective, which describes the achievements recognized by the 2007 ACS Award for Creative Invention, we discuss the discovery of a new synthetic reaction and its translation into a substantially improved method for manufacturing a major pharmaceutical product--the blockbuster anticancer drug, paclitaxel. The role of creativity in the discovery and invention processes is also discussed. As is often the case, chance discovery and serendipitous findings played a role in the evolution of this work.

Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase.

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity.

Novel multisubstrate inhibitors of mammalian purine nucleoside phosphorylase.

In an effort to develop potent multisubstrate-analog inhibitors of purine nucleoside phosphorylase (PNP), three nucleoside phosphonates were designed utilizing structural information from the previously reported structures of complexes of bovine PNP with substrates and products. The nucleoside phosphonates contain an acetal linkage at the O2' and O3' positions and a two-C-atom spacer between the ribose and phosphate moieties. The linkage enables the compounds to simultaneously occupy the purine-, ribose- and phosphate-binding sites.

Selective inhibition of MCF-7(piGST) breast tumors using glutathione transferase-derived 2-methylene-cycloalkenones.

Human glutathione (GSH) transferase (hGSTP1-1) catalyzes the conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones (COMCs) to highly reactive exocyclic enone alkylating agents. In vitro efficacy studies show that the cytotoxicities of the COMCs directly correlate with the level of expression of GSTP1-1 in MCF-7(piGST) versus MCF-7wt breast tumors, indicating that the exocyclic enones are the actual cytotoxic species. The COMCs are a potentially important new class of prodrugs, which can specifically target multi-drug-resistant tumors overexpressing hGSTP1-1.

Three-component condensation leading to beta-amino acid diamides: convergent assembly of beta-peptide analogues.

A Passerini condensation of acyl cyanides, carboxylic acids, and isonitriles has been developed that affords efficient access to functionalized diamides as well as beta-peptides of alpha-hydroxy-beta-amino acids. Such compounds are protease-resistant and form stable helical and sheet structures when incorporated into larger peptides. N-Protected alpha-amino acids and isocyanoesters derived from alpha-amino acids participate in the condensation, leading to alpha/beta peptides embodying the heterogeneous alpha/beta/alpha backbone motif, recent examples of which display antibiotic activity.

Mechanism of the glutathione transferase-catalyzed conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones to GSH adducts.

Human glutathione (GSH) transferase (hGSTP1-1) processes with similar kinetic efficiencies the antitumor agents 2-crotonyloxymethyl-2-cyclohexenone (COMC-6), 2-crotonyloxymethyl-2-cycloheptenone (COMC-7), and 2-crotonyloxymethyl-2-cyclopentenone (COMC-5) to 2-glutathionylmethyl-2-cyclohexenone, 2-glutathionylmethyl-3-glutathionyl-2-cycloheptenone, and 2-glutathionylmethyl-2-cyclopentenone, respectively. This process likely involves initial enzyme-catalyzed Michael addition of GSH to the COMC derivative to give a glutathionylated enol(ate), which undergoes nonstereospecific ketonization, either while bound to the active site or free in solution, to a glutathionylated exocyclic enone. Free in solution, GSH reacts at the exomethylene carbon of the exocyclic enone, displacing the first GSH to give the final product.

An engineered chorismate mutase with allosteric regulation.

Besides playing a central role in phenylalanine biosynthesis, the bifunctional P-protein in Eschericia coli provides a unique model system for investigating whether allosteric effects can be engineered into protein catalysts using modular regulatory elements. Previous studies have established that the P-protein contains three distinct domains whose functions are preserved, even when separated: chorismate mutase (residues 1-109), prephenate dehydratase (residues 101-285), and an allosteric domain (residues 286-386) for feedback inhibition by phenylalanine. By deleting the prephenate dehydrase domain, a functional chorismate mutase linked directly to the phenylalanine binding domain has been engineered and overexpressed.

Reversing the action of noncompetitive inhibitors (MK-801 and cocaine) on a protein (nicotinic acetylcholine receptor)-mediated reaction.

The nicotinic acetylcholine receptor (nAChR) is one of five structurally related membrane proteins required for communication between approximately 10(12) cells of the mammalian nervous system. The receptor is inhibited by both therapeutic agents and abused drugs. Understanding the mechanism of noncompetitive allosteric inhibitors of the nicotinic acetylcholine receptor is a long-standing and intensely investigated problem.

Mapping of chorismate mutase and prephenate dehydrogenase domains in the Escherichia coli T-protein.

The Escherichia coli bifunctional T-protein transforms chorismic acid to p-hydroxyphenylpyruvic acid in the l-tyrosine biosynthetic pathway. The 373 amino acid T-protein is a homodimer that exhibits chorismate mutase (CM) and prephenate dehydrogenase (PDH) activities, both of which are feedback-inhibited by tyrosine. Fifteen genes coding for the T-protein and various fragments thereof were constructed and successfully expressed in order to characterize the CM, PDH and regulatory domains.

Molecular basis of the antitumor activities of 2-crotonyloxymethyl-2-cycloalkenones.

The antitumor activity of 2-crotonyloxymethyl-2-cyclohexenone (COMC-6) is not the result of the GSH conjugate (GSMC-6) formed inside tumor cells, as the diethyl ester prodrug form of GSMC-6 displays little antitumor activity with B16 melanotic melanoma in vitro (IC(50) > 460 microM) versus COMC-6 (IC(50) 0.041 microM) and its five- and seven-membered ring homologues. Antitumor activity probably results from a reactive intermediate that forms during conjugation of the COMCs with intracellular GSH.