Arthur Y. Shaw

Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents.

To continue our early study on the structural modifications of clioquinol, more 8-hydroxyquinoline-derived Mannich bases were synthesized and examined for growth-inhibitory effect. Taken Mannich base 1 as our lead compound, upon replacement of either sulfonyl group with methylene group or piperazine ring with ethylenediamine group resulted in an appreciable increase in potency. On the other hand, as 8-hydroxyquinoline was replaced with phenol, 3-hydroxypyridine and 1-naphthol, a dramatic decrease in activity was observed, indicating that 8-hydroxyquinoline is a crucial scaffold for activity. Further 3D-QSAR analysis on HeLa cells revealed that both steric and electronic effects contributed equally to growth inhibition. Taken together, the structure-activity relationships obtained from both in vitro data and CoMFA model warrant a valuable reference for further study.

Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer.

A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 μM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.

Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines

Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity.

Applications of ortho-phenylisonitrile and ortho-N-Boc aniline for the two-step preparation of novel bis-heterocyclic chemotypes

Concise routes to five pharmacologically relevant bis-heterocyclic scaffolds are described. Significant molecular complexity is generated in a mere two synthetic operations enabling access to each scaffold. Routes are often improved by microwave irradiation and all utilize isocyanide-based multi-component reaction methods to incorporate the required diversity elements. Common reagents in all initial condensation reactions include 2-(N-Boc-amino)-phenyl-isocyanide 1, mono-Boc-phenylenediamine 2 and ethyl glyoxalate 3.

Dyrk1 inhibition improves Alzheimer's disease-like pathology

There is an urgent need for the development of new therapeutic strategies for Alzheimers disease (AD). The dual‐specificity tyrosine phosphorylation‐regulated kinase‐1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD‐like pathology developed by 3xTg‐AD mice, a widely used animal model of AD. We dosed 10‐month‐old 3xTg‐AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1‐inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg‐AD mice. These effects were associated with a reduction in amyloid‐β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.

Beyond secretases: Kinase inhibitors for the treatment of Alzheimer's disease

Abstract Alzheimer’s disease (AD) is the most prevalent form of dementia in old age. Recent data indicate that 24.3 million people worldwide suffer from AD. Hyperphosphorylation of tau, a protein normally involved in microtubule stabilization, has been identified as an important pathological contributor to AD development. In AD brains, hyperphosphorylation of tau leads to its aggregation, misfolding, and formation of neurofibrillary tangles, one common hallmark of AD. Specific protein kinases, such as GSK-3β, CDK5, and DYRK1A, are involved in tau hyperphosphorylation and have been identified as potential targets for the development of novel therapeutic agents for the treatment of AD cognitive deficits. We herein review the current state of the art in the development of small molecule inhibitors of GSK-3β, CDK5, DYRK1A, and other protein kinases involved in tau phosphorylation. Only recently developed compounds with cellular and/or in vivo activity will be discussed.

Synthesis of Di- and Tri-Substituted Imidazole-4-carboxylates via PBu3-Mediated [3 + 2] Cycloaddition

Abstract Some new di- and trisubstituted imidazole-4-carboxylates were prepared from amidoacetic acids 3 in the present report. The key step to establish such imidazole-4-carboxylates stemmed from the PBu3-mediated [3 + 2] cycloaddition between in situ–generated Δ2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisubstituted imidazoles 7–20 were afforded in better yields than those of disubstituted imidazoles 21–27. Supplemental materials are available for this article. Go to the publishers online edition of Synthetic Communications® to view the free supplemental file. GRAPHICAL ABSTRACT

Oxidative Deaminations and Deisatinylations of Ugi-Azide and Ugi-3CR Products: A Two-Step MCR-Oxidation Protocol toward Functionalized α-Ketoamides and α-Ketotetrazoles

A new postcondensation multicomponent reaction (MCR) methodology, comprising oxidative deaminations enabling access to multiple privileged carbonyl-containing scaffolds in two steps, is described. These protocols allow facile access to functionalized α-ketoamide and α-ketotetrazole small-molecule peptidomimetic-like building blocks from prototypical synthons with two points of diversity. Incorporation of chalcone and alkynyl moieties with further ring-forming reactions enables access to additional novel heterocyclic ring systems, including a unique and potentially highly pharmacologically relevant scaffold, a 1,2-selenazol-3(2H)-one.

Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward Vicinal Tricarbonyl Amides: Two-Step MCR-Oxidation Methodology Accessing Functionalized α,β-Diketoamides and α,β-Diketotetrazoles

Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily affords vicinal tricarbonyls (α,β-diketoamides) and α,β-diketotetrazoles with two diversity elements. This significant extension of our previously described multicomponent reaction-oxidative deamination methodology is proposed to proceed through a mechanistically distinct SeO2-mediated C-N oxidation derived from an active enol of α-amino-β-ketone systems, effectively an aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide building blocks in a mere two steps.

Copper(I) catalyzed oxidative hydrolysis of Ugi 3-component and Ugi-azide reaction products towards 2 degrees alpha-ketoamides and alpha-ketotetrazoles

Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(i)-mediated C-N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.