Isolation of a novel substrate‐competitive tyrosine kinase inhibitor, desmal, from the plant Desmos chinensis

Abstract

In the course ot a screening program for tyrosine kinase inhibitors, the chloroform extract of a tropical plant, Desmos chinensis, strongly inhibited the enzyme activity. The active substance was purified by silica gel, gel filtration, and finally crystallized. The structure was elucidated by mass spectrometry and X-ray crystallography to be 8-formyl-2,5,7-trihydroxy-6-methylflavanone, and we named it desmal. Desmal competed with peptide substrate and non-competed with ATP. It inhibited tyrosine kinase in situ in epidennal growth factor (EGF) receptor-overexpressing NIH3T3 (ER12) cells. It also inhibited EGF-induced inositol phosphate formation and morphological changes.

Plant-Derived Protein Tyrosine Kinase Inhibitors as Anticancer Agents

“…In addition, Lineweaver-Burk plotting with histone as a substrate showed that desmal competed with peptide substrate but not with ATP. It was rather unexpected since all very active flavonoids such as genistein (66) and orobol (68) inhibited PTK activity by competing with ATP [136]. A substrate-competitive inhibitor would be advantageous for specific inhibition of PTKs.…”

“…Based on the little effect of genistein on p40 kinase, however, it should be noted that, the use of more enzyme may provide more selective and adequate responses and much lower IC 50 values to assess the potency of flavanones [135]. As an example for this, desmal (65), a flavanon isolated from the chloroform extract of a tropical plant, Desmos chinensis by Kakeya and coworkers, did not inhibit PKC or phosphatidylinositol kinase at 300 µM, but strongly inhibited EGF receptor-associated tyrosine kinase phoshorylation of NIH3T3 (ER12) cells with an IC 50 of 2.5 µg/ml (8 µM) [136]. In addition, Lineweaver-Burk plotting with histone as a substrate showed that desmal competed with peptide substrate but not with ATP.…”

Desmoschinensisflavones A and B, two rare flavones having a hybrid benzyl benzoate ester-flavone structural framework from Desmos chinensis Lour

“…11 Some of these compounds showed antimicrobial, 12 antifungal, 11 antitumor, and acute toxic activities. 13 Of the three different owering species of D. chinensis growing at Mae Fah Luang University, the red, yellow, and giant owering forms, herein, we report the isolation and structure elucidation of two new hybrid benzoate ester-avones (1 and 2) together with 12 known compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) isolated from the fruit, leaf, and twig extracts of the red owering species of D. chinensis. This is the rst report on the isolation of natural products having a hybrid benzyl benzoate ester-avone skeleton from the Annonaceae family to the best of our knowledge.…”

“…For example, the decoction of D. chinensis roots has been used for the treatment of malaria. 8 In India, Malaysia, and Thailand, the roots of D. chinensis have been used to treat diarrhea, dysentery, fever, parturition vertigo, and postpartum pot herbs. 1,9 Previous phytochemical studies on D. chinensis produced several types of compounds, including biavones, 1 benzyl benzoate esters, 10 C-benzylated chalcones, 9 oxoaporphine alkaloids, 10 and avonoids.…”

Mass spectrometric characterization of a series of adenosylated peptides acting as bisubstrate analogs of protein kinases

“…Despite the lack of details of the mechanism and nature of the catalytic site for tyrosine kinases, some significant progress has been made towards the development of inhibitors. For example, several natural products isolated from plants [15) and fungal fermentation broths [16] have been shown to possess inhibitory activity against several growth factor recep• tors. To increase selectivity, efforts have been made to enhance the tyrosine mimetic character of these inhibitors using benzylidene compounds [17) and 4-hydroxycinnamamide derivatives [18,19).…”