At the global pharmaceutical market is rapidly growing the number of therapeutic drugs based on protein kinases inhibitors. Protein kinases are targets for treatment of number diseases, including cancer, diabetes and various processes of inflammation. Scientific interests of group of chemistry of inhibitors of protein kinases are concentrated on the synthesis of new and chemical optimization of known inhibitors of protein kinases. Chemical nature of compounds that are synthesized by our group it’s a derivatives of pyrimidine, indole, benzimidazole, carbazole and imidazolium salts.

Pyrimidine and indole derivatives. Combinatorial series of pyrimidine derivatives with N-alkyl, N-cycloalkyl, N-1H-indol-5-yl substituents at positions 2,4,6 and condensed polycyclic system are synthesized and studied for anticancer activity. With the purpose of obtain of new inhibitors of kinases the synthesis of the indicated derivatives is optimized.

Fig. 1. Pyrimidine and indole derivatives.

Polyhalogenated derivatives of 5-phenylamino-benzimidazol-carboxamide and 2-phenylamino-benzamide. Among well-known inhibitors of protein kinases there are also benzimidazol-carboxamide derivatives. Biological activity of these compounds considerably increases due to introduction of atoms of Fluorine, Bromine and Iodine to the aromatic ring. The chemical optimization of inhibitor structures is performed using computer modeling and biological testing.

Fig. 2. Derivatives of benzimidazol-carboxamide and 2-phenylamino-benzamide

Benzimidazole derivatives and quaternary imidazolium salts. Among the known effective inhibitors of kinases, which were entered in clinical tests, there are derivatives of benzimidazole and imidazolium ionic liquids which are given on fig. 3.

Fig. 3. Benzimidazole derivatives and quaternary imidazolium salts.

Cyclin-dependent kinase 4 (Cdk4) represents a key target for the treatment of cancer. Most human cancers are characterized by over expression of Cdk4’s activating partner cyclin D1, loss of the natural Cdk4-specific inhibitor p16, or mutations in Cdk4’s catalytic subunit. All of these can cause deregulated cell growth with resulting in tumour formation.

A convergent synthetic approach developed by our scientists to get CINK4, a chemical inhibitor of Cdk4, is depicted on the following scheme:

© YARMOLUK RESEARCH LAB