Andrew C. Flick

Synthetic approaches to the 2009 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.

Synthetic approaches to the 2010 new drugs

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.

Synthetic approaches to the 2011 new drugs.

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.

Synthetic approaches to the 2013 new drugs.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review.

Utilization of a Michael Addition: Dipolar Cycloaddition Cascade for the Synthesis of (±)-Cylindricine C

A new approach to the marine alkaloid (+/-)-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting cycloadduct was converted into (+/-)-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation, and conjugate addition to introduce the n-hexyl side chain.

Synthetic approaches to the 2014 new drugs

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.

2,3-Bis(phenylsulfonyl)-1,3-butadiene as a Reagent for the Synthesis of the Azatricyclic Core of (±)-Halichlorine

An efficient stereocontrolled route to the azatricyclic core of an advanced halichlorine intermediate is described. Reaction of the oxime derived from 2-(oxo-cyclopentyl)acetic acid ethyl ester with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to afford a transient nitrone that then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish a spirocyclic piperidinone, which was further elaborated to an advanced intermediate employed in an earlier synthesis of halichlorine.

Application of Cross-Conjugated Heteroaromatic Betaines to the Synthesis of the Schizozygane Alkaloid (±)-Strempeliopine†

An efficient stereocontrolled route to the isoschizozygane alkaloid core has been developed utilizing an intramolecular 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-azaacenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid. A variation of this tactic was then employed for a synthesis of the hexacyclic framework of the shizozygane alkaloid (+/-)-strempeliopine. The key step of the synthesis corresponds to an intramolecular 1,4-dipolar cycloaddition of a heteroaromatic betaine across a tethered 4-((2-nitrophenyl)but-3-enyl) side chain. Catalytic reduction of the nitro group followed by reaction with NBS resulted in the formation of the required pentacyclic indoline framework of the target alkaloid. Closure of the final ring of the shizozygane skeleton was carried using an oxidative cyclization.

Synthetic approaches to the 2012 new drugs

New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.