Dedicated to Prof. Antonio Togni on the occasion of his 65th birthday and retirement New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7piperazine substituted oxazolo[4,5-d]pyrimidines 8a-8c could be potential VEGFR2 inhibitors with high free energy of ligand-protein complex formation (ΔG: À 10.1, À 9.6, À 9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a-8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3] oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate (8c) exhibited a slightly higher antiproliferative effect (IC 50 = 0.21 μM) than doxorubicin (IC 50 = 0.36 μM) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC 50 = 1.7 μM) and HCT-116 (IC 50 = 0.24 μM) cells.

Synthesis of a series of 2-(dichloromethyl)pyrazolo [1,5-a][1,3,5]triazines and evaluation in vitro of their anticancer activity against a panel of 60 cell lines derived from nine cancer types, namely leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer. Methods. Organic synthesis; biological tests; spectral methods; statistical methods. Results. In vitro screening of the anticancer activity showed that 5 of 26 tested compounds can effectively inhibit the growth of certain cancer cell lines. Conclusions. New type of N-(2,2-dichloro-1-cyanoethenyl)carboxamides heterocyclization with 1H-pyrazol-5-amines led to the formation of 2-(dichloromethyl)pyrazolo [1,5-a][1,3,5]triazines. Some of these compounds inhibit growth of certain cancer cell lines.

The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also oc-How to cite this article:

A novel series of 1,3-oxazol-4-yltriphenylphosphonium salts has been synthesized and functionalized. Oxazole derivatives were subjected to NCI in vitro assessment. Seven most active derivatives have been selected for five-dose assay. Among them, compounds 9 and 4 ( [5-phenyl-2-[(4methylphenyl)amino]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) were the most active against all tested cancer subpanels. Statistical analysis of the total panel data showed average values of parameters of anticancer activity in the range of 0.3-1.1 μM (GI 50 ), 1.2-2.5 μM (TGI) and 5-6 μM (LC 50 ). It was found that the presence of phenyl or 4-methylphenyl groups at C(2) and C(5) in the oxazole ring is of critical importance for the manifestation of the anticancer activity. Matrix COMPARE analysis using LC 50 vector showed a high positive correlation of compound 9 with standard anticancer agents that can directly disrupt mitochondrial function, causing programmed death of cancer cells. The obtained results indicate the anticancer activity of 1,3-oxazol-4-ylphosphonium salts, which could be useful for developing new anticancer drugs. The most active of them can be recommended for further in-depth studies and synthesis of new derivatives with antitumor activity on their basis.

: Background: Synthesis of a series of 2-(dichloromethyl)pyrazolo[1,5- a][1,3,5]triazines was carried out and evaluated in vitro for their anticancer activity against a panel of 60 cell lines derived from nine cancer types. The joint quantum-chemical and experimental study of the influence of the extended πconjugated phenyl substituents on the electron structure of the pyrazolo[1,5-a][1,3,5]triazines as Pharmacophores were performed. It is shown that the decrease in the barriers to the rotation of phenyl substituents in compounds 1-7 possibly leads to an increase in the anti-cancer activity, which is in agreement with the change in the parameter biological affinity ϕ0. Analysis of the S0 → S1 electronic transitions (π→π*) of the pyrazolo[1,5-a][1,3,5]triazines shows that an increase in their intensity correlates with anti-cancer activity. Thus, the introduction of phenyl substituents increases the likelihood of investigated pyrazolo[1,5-a][1,3,5]triazines interacting with protein molecules (Biomolecule) by the π stacking mechanism. In both methyl and phenyl derivatives of pyrazolo[1,5-a][1,3,5]triazines, the second electronic transition includes the n-MO (the level of the lone electron pair in two-coordinated nitrogen atoms). The highest intensity of the η→π* electronic transition is observed in pyrazolo[1,5-a][1,3,5]triazine with pyridine residue, which does not exhibit anti-cancer activity, but exhibits antiviral activity [13]. It can be assumed that the possibility of the formation of [Pharmacophore-Biomolecule] complex by hydrogen bonding ([H-B]) mechanism with protein molecules increases.

A novel series of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles has been synthesized, characterized and subjected to NCI in vitro assessment. Cancer cell lines of all subpanels were most sensitive to 2-{[4-[(4-fluorophenyl)sulfonyl]-2-(2furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l). Its antiproliferative and cytotoxic activity averaged over each subpanel was manifested in a very narrow range of concentrations (GI 50 : 1.64-1.86 μM, TGI: 3.16-3.81 μM and LC 50 : 5.53-7.27 μM), i. e. practically did not depend on the origin of the cancer cell line. The COMPARE matrix using TGI vector showed a high positive correlation of 3 l (r = 0.88) with the intercalating agent aclar-ubicin, which inhibits topoisomerases. The absence in the database of standard agents that have a high correlation with the cytotoxicity of this compound suggests that it may have a unique mechanism of action. According to the results of the docking analysis, the most promising anticancer target for compound 3 l is DNA topoisomerase IIβ. The obtained results indicate the anticancer activity of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles, which may be useful for the development of new anticancer drugs. 2-{[4-[(4-Fluorophenyl)sulfonyl]-2-(2-furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l), as the most active, can be recommended for further in-depth studies.

A series of 1,3-oxazolo[4,5-d]pyrimidine and 1,3-oxazolo[5,4-d]pyrimidine derivatives has been synthesized and functionalized. The obtained compounds were tested against breast cancer cell lines of the NCI subpanel, followed by further analysis...

Dedicated to Prof. Girolamo Cirrincione in recognition of his outstanding contributions to the fields of organic and medicinal chemistry on the occasion of his retirement