NOVEL QUINONE ANTIPROLIFERATIVE INHIBITORS OF PHOSPHATIDYLINOSITOL-3-KINASE

The inhibition of phosphatidylinositol-3-kinase (PtdIns-3-kinase), pro tein kinase C and c-Src protein tyrosine kinase by a series of halogen ated naphthoquinones and quinoline quinones related to the plant-deriv ed naphthoquinones juglone and methyljuglone, which inhibit protein ki nase C, has been investigated. Some of the compounds inhibited PtdIns- 3-kinase at micromolar concentrations and below. PtdIns-3-kinase inhib ition was time dependent and could be prevented by endogenous thiol. T he compounds were only weak inhibitors of PtdIns-4-kinase. Some of the compounds inhibited protein kinase C, but c-Src protein tyrosine kina se was only weakly inhibited. In intact cells, PtdIns-3-kinase was onl y partly inhibited by concentrations of the halogenated quinones that inhibited cell growth. Some halogenated quinones showed in vivo antitu mor activity without accompanying toxicity, while methyljuglone was wi thout in vivo antitumor activity. Halogenated quinones may have multip le biochemical effects in the cell that could contribute to their cyto toxic and antitumor effects. Inhibition of PtdIns-3-kinase by the halo genated quinones may provide a lead for the development of more potent and specific inhibitors.