C-3-modified analogues of 1D-myo-inositol as inhibitors of phosphatidylinositol 3-kinase

Author

Tzenge-Lien Shih

Date of Award

5-1992

Degree Type

Thesis

Degree Name

Master of Science

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Ronald M. Magid, Richard M. Pagni

Abstract

The phosphoinositol pathway involves the synthesis of phosphatidylinositol (PtdCMP) from inositol and cytidine diphosphate diglyceride (PtdCMP) via the action of phosphatidylinositol synthetase (EC 2.7.8.11). Phosphorylation of the resulting phosphatidylinositol derivative occurs first at C-4, and then at C-5, via specific enzymes, 1-phosphatidylinositol kinase (EC 2.7.1.67) and 1-phosphatidylinositol 4-phosphate kinase (EC 2.7.1.68), to give phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂]. Signal transduction is mediated by the calcium (Ca²⁺) mobilization, which is also affected by the hydrolysis of PtdIns(4,5)P₂ by phospholipase C (EC 3.1.4.3) to yield inositol 1,4,5 trisphosphate [Ins(l,4,5)P₃] and 1,2-di-O-acylglycerol (A₂Gro). The Ins(l,4,5)P₃can be further phosphorylated by phosphatidylinositol 3-ldnase in certain cell systems. Studies carried out on oncogenic systems, however, suggest somewhat different modes of action. It seems that phosphatidylinositol is first phosphorylated to phosphatidyl inositol 3-phosphate via the action of phosphatidylinositol 3-kinase. The inositol 1,3,4,5- tetrakisphosphate has been shown to be associated with net Ca²⁺ transport across membranes and has some influence on pathophysiological processes, including oncogenesis.

In order to inhibit the activity of Ptdlns 3-kinase, the strategy is that of modifying myo-inositol at the 3-position so that the compounds would retain respectable substrate active with phosphatidyl synthetase, then hope that the resulting phosphatidyl analogues would block the action of this enzyme. myo-Inositol is a meso compound. The advantage in synthesizing optically active D-myo-inositol analogues from an optically active compound, L-quebrachitol [lL-(-)-2-O-methyl-chiro-inositol], instead of myo-inositol itself, is that optical resolution methods are not required to isolate pure enantiomeric products.

The analogues synthesized in this thesis include lD-3-deoxy-myo-inositol (4), 1D- 3-deoxy-4-O-methyl- myo-inositol (5), lD-4-O-methyl-myo-inositol (10), lD-3-chloro-3-deoxy-myo-inositol (14), and lD-3-deoxy-3-mercapto-myo-inositol (17).

Recommended Citation

Shih, Tzenge-Lien, "C-3-modified analogues of 1D-myo-inositol as inhibitors of phosphatidylinositol 3-kinase. " Master's Thesis, University of Tennessee, 1992.
https://trace.tennessee.edu/utk_gradthes/12280