YARMOLUK RESEARCH LAB

The protein kinase CK2 is known to long been implicated in the regulation of cell growth and proliferation. Thus, CK2-kinase inhibitors are considered as potential anticancer drugs.
     According to their chemical structure, the CK2 inhibitors are subdivided into polypeptides, benzoimidazole and benzotriazole derivatives, flavonoids, anthraquinone, quinazoline, isoquinoline, naphthalene, xanthenone and fluorenone derivatives. Such inhibitors TBB, 1,8-dihydroxy-4-nitroxanthen-9-one (V2) and flavonoids fisetin and quercetin are among well-known inhibitors of protein kinase CK2. Their IC50 fre found between 0.3 to 1.6 mM, but their low specificity stimulates a search of new high-specificial CK2 inhibitors, CK2 kinase activity in nanomolar concentrations.
     The Chemistry of Protein Kinase Inhibitors Group carries out the search of potential CK2 inhibitors, which is based on the synthesis of combinatorial libraries of compounds of different chemical nature.
     Different chemical classes of potential CK2 inhibitors are synthesized in our lab and investigated for anticancer activity in National Cancer Institute (USA) (Fig. 1-6).
     4-Aminoquinazolines. Quinazolines, quinolines and thienopyrimidines are synthesized in our lab and investigated to find their anticancer activity. The compounds presented possess have aliphatic and aromatic amines the position 4 (Fig. 1).

Fig. 1. 4-Aminoquinazoline, 4-aminoquinoline and thienopyrimidine derivatives

Isoflavones. Combinatorial series of 7-hydroxy-3-(aryl or aryloxy)-2-trifluoromethyl-4H-4-chromenone derivatives are synthesized collaboration with the Kiev National Taras Shevchenko University (Prof. Khilya V. P.) (Fig. 2). The correlation between chemical structure of compounds synthesized and their anticancer activity was investigated by biological testing in the National Cancer Institute.

Fig. 2. Isoflavones

2,5-Dihydropyrrole-2,5-dione derivatives. Combinatorial series of 2,5-dihydropyrrole-2,5-dione derivatives with various substituents at positions 1,3,4 of pyrrole ring are synthesized and studied for anticancer activity.

Fig. 3. 2,5-Dihydropyrrole-2,5-dione derivatives

[1,3]thiazolo[3,2-b][1,2,4]triazine and [1,3]thiazolo[3,2-a]pyrimidine derivatives. Combinatorial series of condensed thiazoles: [1,3]thiazolo[3,2-b][1,2,4]triazine and [1,3]thiazolo[3,2-a]pyrimidine are synthesized as potential CK2 inhibitors. The chemical optimization of inhibitor structures is performed using computer modeling and biological testing.

Fig. 4. [1,3]Thiazolo[3,2-b][1,2,4]triazine and [1,3]thiazolo[3,2-a]pyrimidine derivatives

Triazine derivatives. Among well-known inhibitors of protein kinases there are also triazine derivatives. We synthesize the range of triazine derivatives to develop new CK2 inhibitors (Fig. 5). Our work is based on computer modeling and biological testing aimed for the optimization of chemical structure of triazines is carried out.

Fig. 5. Triazine derivatives

Pyrrolo[b]pirazine derivatives. Synthesis and optimization of pyrolo[b]pyrazine structure based on computer modeling and biological testing are carried out (Fig. 6).

Fig. 6. Pyrrolo[b]pirazine derivatives