Part~I. Synthesis and protein-tyrosine kinase inhibiting activity of polyhydroxylated stilbene analogues of piceatannol. Part~II. Study of the novel oxidative cyclization of 2'-hydroxychalcones to 4,5-dialkoxyaurones by thallium(III) nitrate

Kshitij Chhabilbhai Thakkar, Purdue University

Abstract

Part I. Protein-tyrosine kinases (PTK's), which catalyze the transfer of the terminal $\gamma$-phosphate of ATP to the phenolic group of tyrosine residues on many essential substrate proteins, play key roles in these signal transduction pathways for regulation of normal cell growth and differentiation. The enzyme chosen for study, p56$\sp{lck},$ is a lymphoid cell lineage-specific PTK of the src family which is overexpressed in several lymphomas. This situation has stimulated a great deal of interest in the development of PTK inhibitors as potential anti-cancer agents. Piceatannol, a known antileukemic principle in the seeds of Euphorbia lagascae, inhibits the PTK activities of p56$\sp{lck}$ by binding to the substrate binding sites. In view of the fact that virtually nothing has been reported on the SAR for the PTK inhibitory activity of piceatannol, a study has been undertaken of the effect of the number and placement of the hydroxyl groups on the trans-stilbene system on the inhibition of p56$\sp{lck}.$ Reduction of the double bond bridging the two aromatic rings and the benzylation of the phenolic groups was found to decrease activity significantly. The most potent compounds in the series proved to be trans-3,3$\sp\prime$,5,5$\sp\prime$-tetrahydroxystilbene, trans-3,3$\sp\prime$,5-trihydroxystilbene, and trans-3,4,4$\sp\prime$-trihydroxystilbene. Part II. Due to our current interest in the synthesis of isoflavones as potential protein-tyrosine kinase inhibitors, the oxidative rearrangement followed by cyclization of 2$\sp\prime$-hydroxychalcones into the corresponding isoflavones by thallium(III) nitrate in methanol was investigated. In the present attempt to synthesize isoflavones, an unusual oxidative cyclization of 2-hydroxychalcones to 3,4-alkoxyaurones was observed instead. Scope and mechanism studies were performed on this novel oxidative transformation. A key feature of the reaction is the incorporation of a solvent-derived alkoxy group at C-4 of the aurone. The thermodynamically more stable Z isomers of the aurones were obtained in all cases. Aurones are formed regardless of whether electron donating or electron attracting groups are present at the para position of the B ring of the starting material.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Organic chemistry|Pharmacology

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