William Harris

Oxidative cyclisations with palladium acetate. A short synthesis of staurosporine aglycone.

Abstract A palladium acetate mediated oxidative cyclisation has been used as the key step for the syntheses of staurosporine aglycone and related analogues.

The bisindolylmaleimide protein kinase C inhibitor, Ro 32-2241, reverses multidrug resistance in KB tumour cells

Abstract Ro 32-2241 is a bisindolylmaleimide that selectively inhibits protein kinase C (PKC) as compared with other protein kinases. Experiments were carried out to examine its potential as a multidrug resistance-reversing agent. Ro 32-2241 inhibited efflux, and increased accumulation, of [3H]-daunomycin in multidrug-resistant (MDR) KB-8-5 and KB-8-5-11 cells and had no effect on drug-sensitive KB-3-1 cells. Ro 32-2241 completely reversed the doxorubicin resistance of KB-8-5 and KB-8-5-11 cells, showing no effect on the sensitivity of drug-sensitive KB-3-1 cells. The potency of Ro 32-2241 was comparable with that of cyclosporin A and better than that of verapamil, known modulators of multidrug resistance. Ro 32-2241 also completely reversed the taxol resistance of KB-8-5 cells and partially reversed the resistance of KB-8-5-11 cells. Vinblastine resistance was also partially reversed. Mechanistic experiments were carried out to determine whether Ro 32-2241 interacted with P-glycoprotein (Pgp) directly. Increased efflux of [14C]-Ro 32-2241 was seen with the more resistant KB-8-5-11 cells (although the percentage effluxed was very low as compared with [3H]-daunomycin), suggesting that Ro 32-2241 can act as a substrate for Pgp. Direct interaction of Ro 32-2241 with Pgp was confirmed by demonstration that it inhibited binding of [3H]-azidopine to Pgp in KB-8-5-11 membranes. In conclusion, Ro 32-2241, acting directly on Pgp (rather than, or in addition to, an effect on PKC), is effective in reducing or reversing resistance to doxorubicin, taxol and vinblastine in human tumour cells with a clinically relevant degree of MDR. However, results of in vivo experiments conducted to investigate the effects of Ro 32-2241 on resistance to doxorubicin suggest that it may not be possible to achieve sufficiently high levels of Ro 32-2241 in vivo to modulate MDR.

Selective tyrosine kinase inhibitors

The tyrosine specific protein kinases (TK) are a subgroup of the largest known gene family, the kinases. Latest estimates suggest that there are over 2000 kinases encoded in the human genome [1]. TKs catalyse the transfer of phosphate to the phenolic hydroxyl of tyrosine residues in substrate proteins, consequently modifying the target protein properties. By working in concert with tyrosine phosphatases, which drive the reverse process, the TKs provide a switching system resulting in the transduction of signals from cell surface receptor to the nucleus. Inappropriate activation of TKs can lead to abnormal, dysregulated cellular proliferation and many of the known oncogenes are kinases. Naturally, there has been great interest in TKs as potential molecular targets for developing drugs for the treatment of cancer and results from the first clinical trials are now being published. Preclinical research is also focused on other therapeutic applications of TK inhibitors. This review concentrates on TK inhibitors which are either already in the clinic or likely to enter Phase I studies in the near future.

Recent developments in protein kinase C inhibitors

The serine/threonine protein kinase isoenzyme family, protein kinase C (PKC), is a group of closely-related enzymes which apparently mediate a range of responses in different cell types. Their involvement in cellular proliferation and differentiation has made inhibitors of these isoenzymes of great interest as potential anticancer agents. This review looks at compounds under investigation by a number of different pharmaceutical companies within the last two years and reports on their effectiveness in models of cell proliferation and multidrug-resistance.

A convenient synthesis of bisindolylmaleimides

Abstract A mild and flexible method for the preparation of bisindolylmaleimides from the corresponding indoles and indole-3-acetimidate esters is described.