Synthesis and aldose reductase inhibitory activity of acetic acid derivatives of pyrrolo[1,2-c]imidazole

Yamawaki, Ichiro; Matsushita, Yoh‐ichi; Asaka, Naomasa; Ohmori, Koichi; Nomura, Naruo; Ogawa, Kazuo

doi:10.1016/0223-5234(93)90016-8

Cited by 18 publications

(23 citation statements)

References 18 publications

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“…A sample of JJ78:1 was initially obtained from a commercial source. To further confirm bioactivity, chemical structure and purity, larger quantities of JJ78:1 were synthesized from ethyl 3,5-dimethyl-1 H -pyrrole-2-carboxylate (1) in line with literature precedent16 (Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…2C), was synthesized as part of an analogue expansion series to further investigate SAR. This third compound set (Table 2 for structures) also included JJ78:13, a derivative of JJ78:1 in which the bridging ketone had been reduced to a methylene group16 and JJ78:14, an analogue bearing a 2′-methoxybenzoyl group in the 4-position of the dimethylpyrrole ring (Table 2). A by-product was isolated during the synthesis of JJ78:14, in which the 2′-methoxy group had been cleaved giving the corresponding phenol JJ78:15, under the reaction conditions.…”

Section: Resultsmentioning

confidence: 99%

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Characterization, chemical optimization and anti-tumor activity of a tubulin poison identified by a p53-based phenotypic screen

et al. 2008

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A robust p53 cell-based assay that exploits p53's function as a transcription factor was used to screen a small molecule library and identify bioactive small molecules with potential antitumor activity. Unexpectedly, the majority of the highest ranking hit compounds from this screen arrest cells in mitosis and most of them impair polymerization of tubulin in cells and in vitro. One of these novel compounds, JJ78:1, was subjected to structure-activity relationship studies and optimized leading to the identification of JJ78:12. This molecule is significantly more potent than the original hit JJ78:1, as it is active in cells at two-digit nanomolar concentrations and shows clear antitumor activity in a mouse xenograft model as a single agent. The effects of nocodazole, a well established tubulin poison, and JJ78:12 on p53 levels are remarkably similar, supporting that tubulin depolymerization is the main mechanism by which JJ78:12 treatment leads to p53 activation in cells. In summary, these results identify JJ78:12 as a potential cancer therapeutic, demonstrate that screening for activators of p53 in a cell-based assay is an effective way to identify inhibitors of mitosis progression and highlights p53's sensitivity to alterations during mitosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Characterization, chemical optimization and anti-tumor activity of a tubulin poison identified by a p53-based phenotypic screen

et al. 2008

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“…Compounds containing structure b can serve as central nervous system (CNS) depressants, analgesics, and receptor antagonists . Compounds c are aldose reductase inhibitors (ARI) and provide therapeutic possibility in the treatment of chronic complications in diabetes . Directed C2–H functionalizations of indole or pyrrole have been successfully exploited to synthesize these polycyclic heterocycles. , Recently, Cui and others reported Rh(III)-catalyzed C2–H arylation using the CONHOMe directing group previously developed in our laboratory .…”

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confidence: 99%

Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5-a]indole and Pyrrolo[1,2-c]imidazole via Aerobic C2–H Functionalizations

et al. 2017

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Here we report an aerobic Pd(0) catalyzed C2-H functionalization of indoles and pyrroles with tethered N-methoxylamide as the directing group. A Pd(0)-initiated mechanism overcomes the directing or poisoning effect from a wide range of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5-a]indole products are transformed to bioactive analogs after one-step manipulations, demonstrating the potential utility of this reaction in drug discovery.

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“…These include molluscicidal,10 antidiabetic,11 and 5HT 3 antagonist12 activities. This indicates the scaffold itself is amenable to interactions in biological systems.…”

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confidence: 99%

“…1 H -Pyrrolo[1,2-c]imidazol-3(2 H )-ones of different kinds have been associated with various types of characteristics in medicinal chemistry. These include molluscicidal, antidiabetic, and 5HT 3 antagonist activities. This indicates the scaffold itself is amenable to interactions in biological systems.…”

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confidence: 99%

Pyrrole-Based Scaffolds for Turn Mimics

Burgess

2011

Org. Lett.

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Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with an idealized type 1 β-turn and with an inverse γ-turn.Placement of a carbonyl group at the 2-or 5-position of a pyrrole arranges the CO and heterocyclic N-in a 1,3-disposition, just like the main-chain CO and N of amino acids. Several groups have seen this as an opportunity to incorporate pyrrole 2-carboxylic acids into peptides as amino acid surrogates.1 Simultaneously, others have used amino acid starting materials for syntheses of pyrroles with protein/peptide-like side chains.2 However, to the best of our knowledge, none of these strategies have used two amino acids to give pyrrole derivatives with two amino acid derived side chains.Our group is interested in molecules that resemble secondary structures by presenting pertinent amino acid side chains, ie minimalist secondary structure mimics.3 We saw the opportunity to build on the insights of others outlined above, to produce analogs of β-turns; specifically compounds 1, that project two amino acid side chains in orientations corresponding to i + 1 and i + 2 residues of a type I β-turn. Moreover, it was anticipated that syntheses of these molecules could be facilitated by numerous new methods that have emerged recently for intramolecular amination of alkynes to produce N-heterocycles via the disconnections shown (Figure 1).4Syntheses of the target compounds 1 began with Weinreb amides5 of Boc-protected amino acids (Scheme 1).6 These were reduced to the corresponding aldehydes, which, without isolation, were immediately reacted with dianionic, Boc-protected alkynes derived from amino acids.7 Several exploratory sets of conditions were employed to effect this transformation, and an alternative route involving formation of propargyl ketones was also investigated (see supporting). The conditions outlined in Scheme 1 were the most effective overall. This is a difficult reaction, because it involves combination of an anionic electrophile with a nucleophile dianion.Sarpong's platinum (2+) mediated cyclizations of propargylic (2-pyridyl)alcohols8 were used as an initial paradigm for formation of pyrroles in this work (Scheme 2a). Scheme 2b reiterates the mechanistic hypothesis outlined by Sarpong et al for their transformation. It

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Synthesis and aldose reductase inhibitory activity of acetic acid derivatives of pyrrolo[1,2-c]imidazole

Cited by 18 publications

References 18 publications

Characterization, chemical optimization and anti-tumor activity of a tubulin poison identified by a p53-based phenotypic screen

Characterization, chemical optimization and anti-tumor activity of a tubulin poison identified by a p53-based phenotypic screen

Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5-a]indole and Pyrrolo[1,2-c]imidazole via Aerobic C2–H Functionalizations

Pyrrole-Based Scaffolds for Turn Mimics

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