Plant-Derived Protein Tyrosine Kinase Inhibitors as Anticancer Agents

Abstract

Protein tyrosine kinases play a fundamental role in signal transduction pathways regulating a number of cellular functions such as cell growth, differentiation and cell death. Tyrosine kinases are, therefore attractive targets for the design of new therapeutic agents, not only against cancer, but also against many other diseases. Numerous tyrosine kinase inhibitors have been discovered by screening of plant extracts based on ethnopharmacological and chemotaxonomical knowledge. Specific screening approaches have led to the isolation of structurally distinct classes of inhibitors, including phenylpropanes, chalcones, flavonoids, coumarins, styrenes, quinones and terpenes. These natural inhibitors have served as valuable leads for further design and synthesis of more active analogues. Many of these inhibitors have also been used in probing the molecular and cellular mechanisms involved in the protein tyrosine kinase mediated signal transduction. In this review, plant-derived protein tyrosine kinase inhibitors and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy.

Characterization of lipophilicity and antiproliferative activity of E-2-arylmethylene-1-tetralones and their heteroanalogues

“…3). Thus, significant differences were detected between the 2 -and 4 -chlor derivatives (5)(6), while the compound with ortho, orthodichlor substituents (9) has been completely separated from the other two dichlor-derivatives having chlor atoms either in para-position and in addition meta-or ortho-position (7)(8). Incorporation of the chlor atom in 2 position (5) affected the shape of the molecule in its inner part turning the molecule more spherical and resulted in smaller k values in comparison with the derivative of chlor atom in positions 4 (6).…”

“…Structural variations of the molecules of Table 1 were limited to the type of the heteroatom incorporated in the alicyclic ring and to the substitution on the aryl ring (R) or the type of the aryl ring itself (9)(10)(11)(12)(13)(14)(15)(16)(17). These variations allowed studying the influence of the substitution not only on the biological activity but on lipophilicity also.…”

“…Recently, Hollósy and Kéri reviewing the major groups of this plant derived protein tyrosine kinase (PTK) inhibitors and candidates [9] assumed that the natural products are suitable for further exploration to obtain novel leads for new molecular entities as therapeutic agents [10] because of their enormous chemodiversity.…”

Natural product chemistry and anticancer drug discovery

“…In addition, as the daily dietary ingestion of fl avonoids has been estimated at several hundred milligrams, the compounds are considered extremely safe. In the specifi c instance of cancer, fl avonoids have been shown to act through a number of different mechanisms, including antioxidant properties, topoisomerase inhibition, antimitotic activity, kinase inhibition, estrogen antagonism, and modulation of multi-drug resistance (Ren et al, 2003;Hollosy and Keri, 2004). Based on this range of activities, and the varied structures studied, a comprehensive review of the SAR of this class of compounds is beyond the scope of this chapter.…”

Resorcylic acid lactones as new lead structures for kinase inhibition

“…Staurosporine itself, although a potent kinase inhibitor, is too toxic to be therapeutically useful, which is likely the result of its indiscriminate action on a multitude of kinases. While a number of other natural products have been reported to be more or less potent kinase inhibitors [10], the most exciting group of natural products that have recently emerged as new lead structures for kinase inhibition are resorcylic acid lactones 1e4 and, to a somewhat lesser extent, also aigialomycin D (5) (Fig. 1) [11].…”