Novel indole inhibitors of IMPDH from fragments: Synthesis and initial structure–activity relationships

Beevers, Rebekah E.; Buckley, George M.; Davies, Natasha; Fraser, Joanne L.; Galvin, Francis C.; Hannah, Duncan R.; Haughan, Alan F.; Jenkins, Kerry; Mack, Stephen R.; Pitt, William R.; Ratcliffe, Andrew J.; Richard, Marianna D.; Sabin, Verity; Sharpe, Andrew; Williams, Sophie C.

doi:10.1016/j.bmcl.2006.01.090

Cited by 18 publications

(7 citation statements)

References 3 publications

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“…Recently, IMPDH has also become an attractive target for anticancer therapy. Several IMPDH inhibitors (Benzamide riboside, tiazofurine and MPA) (Figure 5) demonstrated high efficiency in preclinical studies [159, 165, 166, 167] and are currently undergoing clinical trials for the treatment of acute and chronic myelogenous leukemia (AML, CML). As IMPDH2 expression increases resistance to MTX, there is a possibility that application of IMPDH inhibitors can enhance the efficiency of MTX-related drugs [160].…”

Section: Other Inhibitors Of Metabolismmentioning

confidence: 99%

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

et al. 2017

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Cancer-related metabolism has recently emerged as one of the "hallmarks of cancer". It has several important features, including altered metabolism of glucose and glutamine. Importantly, altered cancer metabolism connects different biochemical pathways into the one fine-tuned metabolic network, which stimulates high proliferation rates and plasticity to malignant cells. Among the keystones of cancer metabolism are one-carbon metabolism and nucleotide biosynthesis, which provide building blocks to anabolic reactions. Accordingly, the importance of these metabolic pathways for anticancer therapy has well been documented by more than fifty years of clinical use of specific metabolic inhibitors -methotrexate and nucleotides analogs. In this review we discuss one-carbon metabolism and nucleotide biosynthesis as common and specific features of many, if not all, tumors. The key enzymes involved in these pathways also represent promising anti-cancer therapeutic targets. We review different aspects of these metabolic pathways including their biochemistry, compartmentalization and expression of the key enzymes and their regulation at different levels. We also discuss the effects of known inhibitors of these pathways as well as the recent data on other enzymes of the same pathways as perspective pharmacological targets.

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Section: Other Inhibitors Of Metabolismmentioning

confidence: 99%

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

et al. 2017

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“…Cyanoindole and pyridylindole frameworks have so far yielded weaker inhibitors (e.g., compounds 11 and 12 , Chart 5) with weak immunosuppressive activity 190,191. The SAR of these inhibitors differs significantly from their oxazole and urea analogs, which suggests that these inhibitors may have a different binding mode.…”

Section: Inhibitors Of Impdhmentioning

confidence: 99%

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

2009

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“…Thus, quantitative pharmacophore modelling was carried out. Twenty‐five IMPDH inhibitors (19–37) with sufficient diversity in bioactivity and structure were selected to form a training set to generate a pharmacophore model based on their activity values (IC 50 ). Their IC 50 ranged from 4 n m to 32 μ m .…”

Section: Methodsmentioning

confidence: 99%

“…A good pharmacophore is not only able to predict the activity of the training set compounds correctly, but also capable of predicting the activity of external compounds to the training set. To validate the pharmacophore model obtained, we selected 75 IMPDH inhibitors [26–100 (19–37)] as the test set for the pharmacophore model. The structures and activities are shown in Scheme S1 and Tables S1, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…There has been significant success in the discovery of IMPDH‐targeted drugs thus far (10–37). Several compounds such as amides (19), oxazolyl indoles (20), phenyl‐amino oxazoles (21), guanidines (23), triazines (24), isoquinoline aminooxazoles (26), quinolones (28,31), quinazolinones (33), quinazolinethiones and quinazolinediones (34), indoles (35,36), acridones (37) have been reported to inhibit IMPDH activity at low micromolar concentrations. The increasing knowledge base of the IMPDH structure, activity and regulation lays foundation for summarizing essential chemical feature, which may inspire the development of novel IMPDH inhibitors.…”

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confidence: 99%

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A Three‐Dimensional Pharmacophore Model for IMPDH Inhibitors

Yang

Wang

et al. 2011

Chem Biol Drug Des

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Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial and anticancer therapeutic areas. In this study, a chemical feature-based pharmacophore model of IMPDH inhibitors has been firstly developed with the aid of the HypoRefine protocol within Discovery Studio 2.5. The best model for IMPDH inhibitors, Hypo1-1, was characterized by the best correlation coefficient (0.97595) and the lowest RMSD (0.582058). It consisted of one hydrogen-bond donor, one hydrogen-bond acceptor, one aromatic ring and one hydrophobic feature, as well as two excluded volumes. The model was validated using a wide range of test molecules and a cross-validation. Furthermore, the pharmacophore features were confirmed by molecular docking studies. The pharmacophore model could quantitatively predict inhibitor activity and identify highly potent molecules. Therefore, the present results could be valuable for the discovery and development of specific IMPDH inhibitors.

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Novel indole inhibitors of IMPDH from fragments: Synthesis and initial structure–activity relationships

Cited by 18 publications

References 3 publications

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

A Three‐Dimensional Pharmacophore Model for IMPDH Inhibitors

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