Asterriquinones Produced by Aspergillus candidus Inhibit Binding of the Grb-2 Adapter to Phosphorylated EGF Receptor Tyrosine Kinase.

Abstract

Five new asterriquinone analogs (2~4, 6, 7), together with previously identified neoasterriquinone (1) and isoasterriquinone (5), were isolated from a fermentation broth of the fungus Aspergillus candidus and purified by HSCCC(high speed counter current chromatography) followed by HPLC. The structures were determined by ID and 2D NMR and MS/MStechniques. All seven showed inhibitory activity against the binding of a recombinant protein containing the SH2 protein domain of Grb-2 to the tyrosine phosphorylated form of the EGFreceptor tyrosine kinase. Someof these asterriquinones exhibited specific inhibition of Grb-2 binding compared to Grb-7 and PLC-y.In this present study, we sought to identify non-

Electrochemical synthesis of new coumarin derivatives of potential biological significance

“…Diagnostic criteria of cyclic voltammetry and controlled potential coulometry accompanied by spectroscopic data (IR, 1 H NMR, 13 such as hydroxylation [17,18], dimerization [19,20], oxidative ring cleavage [21][22][23] and hydrolysis [24,25], leading to the 4a,b. The oxidation of this compound (4a,b) is easier than the oxidation of the starting molecule (1) by virtue of the presence of an electron-donating group [26].…”

“…At the end of electrolysis the precipitated solid was collected by filtration and washed several times with water. Products were characterized by IR, 1 H NMR, 13 C NMR, and MS. The isolated yields of 8a and 8b are shown in Scheme 1.…”

“…For example, asterriquinone A1 ( Fig. 1), has been shown to arrest the cell cycle in G 1 and promote apoptotic cell death [13][14].…”

Discovery of a Small Molecule Insulin Receptor Activator

“…Some of them are also HIV-l protease inhibitors (Fredenhagen et al, 1997), antibacterial, and toxic to insects (De Guzman et al, 1994). Other biological activities reported for these molecules include inhibition of epidermal growth factor receptor (EGF-R) tyrosine kinase (Fredenhagen et al, 1997) and inhibition of the binding of the Grb-2 adapter to phosphorylated EGFR tyrosine kinase (Alvi et al, 1999). The compound found in our screening previously had been obtained by chemical treatment of asterriquinone Bl (Arai et al, 198 1 b) but its insulin-mimetic properties were unknown.…”

Protein Kinase Inhibitors from Microorganisms

“…Since then several benzoquinones, such as asterriquinones [81][82][83][84] (76)(77)(78)(79)(80)(81)(82)(83)(84), isocochliodinol (85), semicochliodinols (86, 87) [89], and terphenylquinones (88)(89)(90)(91)(92), were isolated [90][91][92]. Although asterriquinones were well recognized for their antibiotic and antitumour activity [87], it took around 25 years to realize their kinase inhibitory potential [85,86,88]. The bioactivity profiling of these derivatives clearly showed that the presence of the 2,5 dihydroxy groups and which of either an indol or a phenol on 3 and 6 positions, in the benzoquinone, is necessary for bioactivity.…”