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We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A(1) adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A(1) AR antagonists taken from the literature and a model of the putative A(1) receptor. The pharmacophore model consists of seven features and represents an improvement of the N(6)-C8 model, generally reported as the most probable pharmacophore model for A(1) AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A(1), A(2a), and A(3) AR, showing interesting antagonistic activity and A(1) selectivity.

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We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.

A number of 4-aminopyrazolo[3,4-b]pyridines 5-carboxylic acid esters (2-8) were synthesized and evaluated for their binding affinity at the A1, A2A, and A3 adenosine receptors (AR), in bovine cortical membranes, as well as for their affinity toward human A1AR (hA1AR). Some of the new compounds were characterized by a high affinity and selectivity toward the A1 receptor subtype, showing a significant improvement in comparison with other pyrazolo-pyridines previously reported in the literature. In particular the methyl ester 2h as well as the isopropyl ester 5h, both of them bearing a p-methoxyphenylethylamino side chain at the position 4, presented Ki values of 6 and 7 nM, respectively. To rationalize the relationships between structure and affinity of the novel compounds, a 3D QSAR model was also generated starting from compounds belonging to different classes of known A1AR antagonists.

Reaction of open‐chain and cyclic sym‐1,3‐diones with N,N‐dimethylformamide dimethyl acetal gave, generally in high yield, a series of sym‐2‐dimethylaminomethylene‐1,3‐diones which reacted with phenylhydrazine and methylhydrazine to afford, generally in satisfactory yield, a number of 1,5‐disubstituted 4‐acylpyrazoles. The applications and limits of this new pyrazole synthesis are presented and discussed.

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Novel 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines are reported with preliminary in vitro activity data indicating that several of them are potent inhibitors (better than the reference compound) of Src phosphorylation of the breast cancer cells 8701-BC, known to overexpress Src. The ability of such compounds to significantly reduce 8701-BC cell proliferation suggests that this scaffold could be a promising lead for the development of antitumoral agents able to block Src phosphorylation of breast cancer cells.