| Abstract [eng] |
Cancer is one of the most topical diseases of society. At present cancer is usually treated by radiotherapy and chemotherapy. Cancer cells are developing from the normal ones, so for a long time it was not easy to identify the possible site of action of anticancer drugs. For this reason, a majority of traditional anti-cancer drugs (DNA-intercalators, DNA-alkylating agents, etc) kill not only cancer cells, but normal-cells as well. Thus, the effectiveness of such drugs can be monitored only if the malignant cells grow and multiply much faster than healthy, which, unfortunately, is not always valid for all cancer strains. For this reason, traditional anticancer drugs always cause side effects, mainly - weakening of the patient's immune system. At the end of the XX century a new era of chemotherapy, based on cell chemistry and biochemistry, began. In recent years numerous genes and proteins that are causally involved in the initiation and progression of cancer have been identified. Based on these discoveries, has been the possibility to develop new drugs, which blocked certain process of cancer cells. In that case are suppressed division and growth of cells. These anticancer drugs are usable for targeted therapy. Theory of cancer biology explained that one of the ways to overcome this disease is the suppressing proliferation of cancer cells. The pyrrolo[3,2-d]pyrimidine heterocyclic framework constitutes the basis of an important class of compounds possessing remarkable biological activities. These compounds are 9-deazaanalogues of biogenic purines and have been reported to be inhibitors of purine nucleoside phosphorylase and thymidylate synthase; in addition to antagonists of the neuropeptide Y5, and the A1 and A2 adenosine receptors. The main aims of present investigation were to synthesize a variety of pyrrolo[3,2-d]pyrimidin-7-one 5-oxides and their structural analogues; to study chemical properties of the title compounds and to evaluate their antiprofilerative activity together with structure-activity relationships. The main results obtained in this work are as follows: It was found, that 6-arylethynyl-5-nitropyrimidines and 2-arylethynyl-3-nitropyridines undergo pyridine-catalysed intramolecular cyclization reactions to form pyrrolo[3,2-d]pyrimidine 5-oxides and pyrrolo[3,2-b]pyridin-3-one 1-oxides, respectively. On the other hand, 1,2-alkoxy-5-phenylethynyl-4-nitrobenzenes underwent cycloizomerization reaction to 3H-indol-3-one 1-oxides only in the presence of transition metal salts. Moreover, the triple bond of 6-arylethynyl-5-nitropyrimidines is easily attacked by primary and secondary amines form syn- (in the case of secondary amines) or anti-addition (in the case of primary amines) products. A novel, simple and high-yielding synthetic method of pyrrolo[3,2-d]pyrimidine framework via one-pot reaction of 2,4-disubstituted 6-arylethynyl-5-nitropyrimidines with secondary amines, followed by reductive cyclization has been developed. It was found, that reduction of pyrrolo[3,2-d]pyrimidin-7-one 5-oxides and pyrrolo[3,2-b]pyridin-3-one 1-oxides led to the formation of the corresponding 5H-pyrrolo[3,2-d]pyrimidin-7-oles and 1H-pyrrolo[3,2-b]pyridin-3-oles. A relatively short and efficient synthetic method of preparing 2,4-disubstituted 6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides through one-pot oxidation/substitution of methylthio group at the 2nd position of the pyrrolo[3,2-d]pyrimidine heterosystem was developed. In vitro antiproliferative activities of synthesized compounds were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D and WiDr. The in vitro experiments show that the most active compounds are disubstituted 6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides containing N-alkylamino or N,N-dialkylamino substituents in the 2nd position of the pyrrolo[3,2-d]pyrimidine heterosystem. Cell cycle studies demonstrate arrest in the G2/M phase when the breast and lung cancer cells were exposed to the most active compound. |
