Anton V. Dolzhenko

Pyrazolo[1,5-a][1,3,5]triazines(5-Aza-9-deazapurines): Synthesis and Biological Activity

The present review gives an account on the synthetic routes to pyrazolo(1,5-a)(1,3,5)triazine system, which is an isostere of purine, and polyfused systems bearing this heterocy clic core. Data concerning biological activity of compounds with pyrazolo(1,5-a)(1,3,5)triazine skeleton are also discussed.

1,2,4-Triazolo[1,5-a][1,3,5]triazines(5-Azapurines): Synthesis and Biological Activity

The present review gives an account of the various synthetic routes to the 5-aza-analogue of purine-1,2,4-triazolo[1,5-a][1,3,5]triazine nucleus and polyfused systems bearing this heterocyclic core. Data concerning biological activity of the compounds with l,2,4-triazolo[l,5-a][l,3,5]triazine skeleton are also discussed.

The significance of 2-furyl ring substitution with a 2-(para-substituted) aryl group in a new series of pyrazolo-triazolo-pyrimidines as potent and highly selective hA3 adenosine receptors antagonists: new insights into structure-affinity relationship and receptor-antagonist recognition

Among the heterocyclic structures identified as potent human A(3) (hA(3)) adenosine receptors antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C(2)-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA(3) receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, K(i) hA(3) = 0.108 nM; hA(1)/hA(3) = 5200; hA(2A)/hA(3) = 7200), in comparison to the C(2)-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A(3) receptor derived from the crystallographic structure of human A(2A) receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes.

1,3,5-Triazine-based analogues of purine: from isosteres to privileged scaffolds in medicinal chemistry.

Purines can be considered as the most ubiquitous and functional N-heterocyclic compounds in nature. Structural modifications of natural purines, particularly using isosteric ring systems, have been in the focus of many drug discovery programs. Fusion of 1,3,5-triazine ring with pyrrole, pyrazole, imidazole, 1,2,3-triazole or 1,2,4-triazole results in seven bicyclic heterocyclic systems isosteric to purine. Application of the isosterism concept for the development of new compounds with therapeutic potential in areas involving purinergic regulation or purine metabolism led to significant advances in medicinal chemistry of the azolo[1,3,5]triazines. These 1,3,5-triazine-based purine-like scaffolds significantly increase level of molecular diversity and allow covering chemical space in the important areas of medicinal chemistry. Some of these azolo[1,3,5]triazine systems have become privileged scaffolds in the development of inhibitors of various kinases, phosphodiesterase, xanthine oxidase, and thymidine phosphorylase, antagonists of adenosine and corticotropin-releasing hormone receptors, anticancer and antiviral agents.

Synthesis of 5,7-Diamino[1,2,4]triazolo[1,2-a][1,3,5]triazines via Annulation of 1,3,5-Triazine Ring onto 3(5)-Amino-1,2,4-trizoles

The 5,7-diamino[1,2,4]triazolo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine. The substituted 3(5)-amino-1,2,4-triazoles were prepared from corresponding hydrazides and S-methylisothiourea via ring closure of the intermediate acylaminoguanidines. The 3,5-diamino-1,2,4-triazoles were prepared using partial aminolysis of dimethyl N-cyanodithiocarbonimidate followed by cyclization of the obtained N-substituted N’-cyano-S-methylisothioureas with hydrazine. The structures of the prepared compound were confirmed using NMR spectral data.

Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors

5-Chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines were designed as new thymidine phosphorylase inhibitors based on the fragment based drug design approach. Multiple-step convergent synthetic schemes were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was synthesized by a 4-step reaction. A series of the second bicyclic intermediates, namely pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one, was obtained from various substituted 3-aminopyrazoles. These two intermediates were coupled finally in the presence of sodium ethoxide and methanol to yield the desirable target compounds. The methylthio coupling spacer was found to be suitable in enabling the interaction of the two fragments at the active site and allosteric site of the enzyme. The best coupled compound (9q) inhibited the thymidine phosphorylase with an IC₅₀ value as low as 0.36 ± 0.1 μM. In addition, 9q demonstrated a mixed-type of enzyme inhibition kinetics, thus suggesting that it might indeed potentially bind at two different sites on the enzyme.

Influence of viscosity and uronic acid composition of alginates on the properties of alginate films and microspheres produced by emulsification

This study investigated the influence of viscosity and uronic acid composition of alginates on the properties of alginate films and microspheres produced by emulsification. Tensile properties of films were determined while the yield, size, drug contents and release characteristics of the microspheres were examined. Tensile properties of calcium alginate matrix were significantly affected by the orientation and arrangement of the polymer chains. High viscosity alginates gave rise to higher yields and bigger microspheres. Generally, microspheres with high drug content and slower rate of drug release had high Ca2+ contents and were produced from alginates of higher viscosity. Within an alginate microsphere batch, small sized microsphere fractions had higher drug contents but showed faster drug release rates. Microspheres having a defined size range revealed great dependence of encapsulation efficiency and drug release rates on viscosity and extent of Ca2+-alginate interaction. Viscosity appeared to exert a predominant influence on the microsphere properties.

Synthesis and Heterocyclizations of 3,4-Dihydroquinazolin-2-yl Guanidine in the Search of New Anticancer Agents

The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate, diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were found to afford 1,3,5-triazino[2,1-b]quinazolines. However, some unexpected reactions were also observed. The structural properties such as tautomerism and hinderance to conformational rotation were also investigated. The results of biological testing suggested that the 1,3,5-triazino[2,1-b]quinazoline nucleus could be a new promising scaffold for the development of potential anticancer agents.

Synthesis and in vitro Evaluation of 1,2,4-Triazolo[1,5-a][1,3,5]triazine Derivatives as Thymidine Phosphorylase Inhibitors

In our lead finding program, a series of 1,2,4‐triazolo[1,5‐a][1,3,5]triazine derivatives were synthesized, and their in vitro thymidine phosphorylase inhibitory potential was explored. Among the different derivatives, compounds having keto group (C = O) at C7 and thioketo group (C = S) at C5 positions showed varying degrees of TP inhibitory activity comparable with positive control, 7‐deazaxanthine (7‐DX, 2) (IC50 value = 42.63 μm). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed‐type inhibitor of the enzyme with respect to thymidine (dThd) as a variable substrate. Compound IVn was also found to inhibit PMA‐induced MMP‐9 expression in MDA‐MB‐231 cells at sublethal concentrations. Computational docking study was performed to illustrate the enzyme inhibition kinetics and to explore the ligand–enzyme interactions.

An efficient synthesis of 2,4,7-trisubstituted pyrimido[1,2-a][1,3,5]triazin-6-ones

A method for the preparation of novel pyrimido[1,2-a][1,3,5]triazin-6-one derivatives functionalized in positions 2, 4, and 7 of the ring was developed. Diversity in the derivatization of the pyrimido[1,2-a][1,3,5]triazin-6-one scaffold was successfully achieved by the introduction of substituents into positions 2 and 7 via two complementary approaches for the synthesis of key intermediates viz. pyrimidinylguanidines. Variations in position 4 of the pyrimido[1,2-a][1,3,5]triazine ring were made available by the regioselective introduction of various substituents via the triazine ring closure with corresponding aldehydes. The scope of the method was illustrated by the preparation of a library of 66 pyrimido[1,2-a][1,3,5]triazin-6-ones, which was demonstrated to be a source for new selective anticancer agents. Tautomeric preferences and anticancer properties were also explored for the prepared compounds.