Copper(i) catalyzed oxidative hydrolysis of Ugi 3-component and Ugi-azide reaction products towards 2° α-ketoamides and α-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.

MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines.

A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first in class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles.

Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles.

This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine was used as an ammonia equivalent in combination with arylglyoxal and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold .

Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines.

A facile and expeditious synthetic approach to α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation.

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.

Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles.

This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with potential to be of interest in future library enrichment strategies.

Facile and rapid route for the synthesis of novel conformationally constrained norstatine analogs via PADAM-cyclization methodology.

The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction - Amine Deprotection - Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

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.

Identification of novel DNA methylation inhibitors via a two-component reporter gene system.

Background: Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation.

Two step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines.

A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.

3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents.

The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 bearing a 1,1'-biphenyl moiety displayed the most potent activity against OVCA, SW620, H460 and AGS cells with GI(50) values of 0.

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.

Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation.

In the present study, we carried out Mannich-type reaction to synthesize clioquinol-derived 7-methyl-arylsulfonylpiperazine analogs with improved growth-inhibitory effects. 11 bearing 5-nitro group on the quinoline ring exhibited 26-fold more potent than that of clioquinol against HeLa cells with a GI(50) value of 0.71 microM.

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.

Synthesis of 2-styrylchromones as a novel class of antiproliferative agents targeting carcinoma cells.

A series of 2-styrylchromone analogs were synthesized and examined for their antiproliferative effects on a panel of carcinoma cells. Among the tested agents, only 4m exhibited a moderate activity with an IC(50) value of 28.9 microM against PC-3 cells which indicates the selectivity of PC-3 cells in response to 2-styrylchromones.