With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as 'non drug-like'. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and 'biotech' therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions.
A novel application of the TMSN3-modified Passerini three-component reaction is disclosed for the rapid solution phase synthesis of cis constrained norstatine mimetic libraries. The reaction of an N-BOC-α-amino aldehyde, an isocyanide and trimethylsilylazide in dichloromethane, followed by deprotection and N-capping with TFP esters affords cis constrained norstatine mimetics. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for protease targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.
The novel solution-phase syntheses of arrays of biologically relevant indazolinones, benzazepines and benzoxazepines, utilizing multi-component condensation (MCC)/SNAr methodology is reported. Reaction of commercially available 2-fluoro-5-nitrobenzoic acid with an aldehyde, isonitrile and a primary amine tethered to a Boc-protected internal amino or hydroxyl nucleophile, affords the Ugi product in good yield. Subsequent acid treatment followed by proton scavenging promotes cyclization of internal amino nucleophiles to a variety of ring sizes. Base treatment alone is sufficient to generate benzoxazepines. Interestingly, this communication also introduces a highly efficient two-step route to benzimidazoles. © 2001 Elsevier Science Ltd.
This communication reveals a novel multicomponent oxidation of saturated, urethane protected nitrogen heterocyclic systems. The oxidation is facile, general, high yielding and involves the application of readily-made hypervalent iodine reagents, giving an α,β,β-oxidation pattern relative to the nitrogen of the heterocycle. The oxidation is multicomponent type III, in that the substrate, reagent and solvent provide the three inputs during the reaction. The transformation also represents an example of triple C-H bond activation. A mechanistic rationale for this is proposed. © 2005 Elsevier Ltd. All rights reserved.
PMID: 23173067;PMCID: PMC3503344;Abstract:
With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimers disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimers disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimers disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. © 2012 American Chemical Society.