Methyl Scanning:  Total Synthesis of Demethylasterriquinone B1 and Derivatives for Identification of Sites of Interaction with and Isolation of Its Receptor(s)

Pirrung, Michael C.; Liu, Yufa; Deng, Liu; Halstead, Diana K.; Li, Zhitao; May, John F.; Wedel, Michael; Austin, Darrell A.; Webster, Nicholas J. G.

doi:10.1021/ja044325h

Cited by 74 publications

(58 citation statements)

References 37 publications

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“…Our finding that the 7-prenyl-indole ring is the active substructure of DAQ-B1 confirms our previous conclusion from a methylation-scanning study of the parental compound. In that study, we found that methyl substitution on the 7-prenyl-indole ring was not tolerated; however, methyl substitution on the 2 isoprenylindole ring did not alter activity (Pirrung et al, 2005). We concluded that the 7-prenyl-indole, but not the 2-isoprenylindole, probably makes close contacts with the insulin receptor kinase domain.…”

Section: Discussionmentioning

confidence: 86%

Identification of Novel Orally Available Small Molecule Insulin Mimetics

Lin

Li²,

Park³

et al. 2007

J Pharmacol Exp Ther

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Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.Orally available insulin analogs would be an enormous benefit to the millions of diabetics who rely on painful regimens of daily insulin injections. In 1999, demethylasterriquinone-B1 (DAQ-B1) was identified as a small, cell-permeable activator of the insulin receptor. This compound was isolated from the fungus Pseudomassaria (Zhang et al., 1999) and is closely related to a large family of Aspergillus terreus natural products (Arai and Yamamoto, 1990;Kaji et al., 1994). These compounds have an unusual tripartite bis-indolyl-dihydroxybenzoquinone structure. DAQ-B1 does not compete with insulin binding but acts directly on the intracellular tyrosine kinase domain of the receptor and furthermore can activate the recombinant IR kinase domain in vitro. Although selective for the IR, DAQ-B1 also activates the insulin-like growth factor-1 receptor (IGF-IR), the nerve growth factor receptor, or epidermal growth factor receptor (EGFR) at 3 to 10-fold higher concentrations (Liu et al., 2000;Wilkie et al., 2001). It stimulates glucose uptake in rat adipocytes and mouse soleus muscle and shows oral antidiabetic activity in ob/ob and db/db mice. Interestingly, DAQ-B1 does not have a mitogenic effect on vascular smooth muscle cells (Weber et al., 2000). DAQ-B1 suppresses neuropeptide Y and stimulates pro-opiomelanocortin gene expression in rats and reduces 24-h food intake and body weight, without causing taste aversion (Air et al., 2002;Obici et al., 2002).A second generation IR activator (Cpd.2) was subsequently identified with slightly greater potency and higher specificity (Liu et al., 2000;Wood et al., 2000). This compound has good pharmacokinetics in preclinical studies in rats, dogs, and monkeys. The addition of Cpd.2 to food prevents increased food intake and weight gain when normal mice are placed on a high fat diet for 7 weeks (Air et al., 2002;Strowski et al., 2004). No toxic effects were observed in treated mice, and

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Section: Discussionmentioning

confidence: 86%

Identification of Novel Orally Available Small Molecule Insulin Mimetics

Lin

Li²,

Park³

et al. 2007

J Pharmacol Exp Ther

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“…1B). Details of the synthetic route have been published previously (Pirrung et al, 2005b). Aliphatic, aromatic, and halogen substitutions were included at different positions on the indole rings and the hydroxyl of the quinone ring, generating 14 possible substitution positions ( Fig.…”

Section: Screening Combinatorial Libraries For Activation Ofmentioning

confidence: 99%

Neuroprotection by Small Molecule Activators of the Nerve Growth Factor Receptor

Lin¹,

Pirrung²,

Deng³

et al. 2007

J Pharmacol Exp Ther

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There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. However, the blood-brain barrier presents a major hurdle in the use of peptide therapeutics. The goal of this study was to identify small molecule, cellpermeable nerve growth factor (NGF) activators. Combinatorial libraries of asterriquinones (Ͼ300) and mono-indolyl-quinones (Ͼ60) were screened using a 96-well enzyme-linked immunosorbent assay that detects phosphorylated TrkA, the NGF receptor. The libraries were also screened for dose-dependent cytotoxicity. From these screens, we generated quantitative structure-activity relationship models for activity and toxicity, and then we selected two compounds, 2-(6-chloro-1H-indol-3-yl)-5-(2-cyclopropyl-1H-indol-3-yl)-3,6-dihydroxy-[1,4]benzoquinone (1H5) and 2,5-dimethoxy-3-(7-fluoro-1H-indol-3-yl)-[1,4]-benzoquinone (5E5), for further study based on high activity and low toxicity. Compound 1H5 (30 M) is an asterriquinone that is a moderate TrkA activator (50% the activity of 100 ng/ml NGF), and it shows little toxicity at concentrations up to 100 M. 1H5 can protect differentiated PC12 neurons from apoptotic cell death induced by NGF withdrawal. Compound 5E5 (30 M) is a mono-indolyl-quinone that is a very strong activator of TrkA (Ͼ200% the activity of 100 ng/ml NGF), and it is nontoxic at concentrations up to 10 M. Activation of TrkA can be detected at 1 M 5E5, and 3 to 10 M 5E5 activates TrkA and extracellular signal-regulated kinase as strongly as a maximal dose of NGF (100 ng/ml). A combination of a low dose of 5E5 (1 M) with a submaximal dose of NGF (10 ng/ml) promotes neuronal differentiation of PC12 cells. These compounds represent a new class of TrkA activators that could have potential utility in the treatment of neurodegenerative diseases.

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“…More recently, Pirrung reported the synthesis of bis(indolyl)-1,4-benzoquinone under relatively intense reaction conditions: using Zn(OTf) 2 (1 equiv.) as catalyst and THF as solvent, refluxing for 26 h under nitrogen followed by oxidation with DDQ, [12] or by coupling with mercury reagents catalyzed by Pd II /Cu-(OAc) 2 . [13] We report herein a highly efficient "on water"-promoted direct coupling of indole compounds with 1,4-benzoquinones (Scheme 1) without the use of any catalyst, additive, or organic solvent.…”

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confidence: 99%