GETAWAY descriptors to predicting A(2A) adenosine receptors agonists.

The GEometry, Topology and Atom-Weights AssemblY approach has been applied to the study of the A(2A) adenosine receptors agonist effect of 29 adenosine analogues: N(6)-arylcarbamoyl, 2-arylalkynyl-N(6)-arylcarbamoyl, and N(6)-carboxamido derivatives. A model able to describe more than 77% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, no one of four different approaches, including the use of Topological, Galvez Topological Charges indexes, Geometrical and WHIM descriptors were able to explain more than 70% of the variance in the mentioned property with the same number of variables in the equation.

Synthesis of carbocyclic analogues of MECA and NECA 1,2-disubstituted as potential adenosine receptor agonists.

A new class of 1,2-disubstituted carbocyclic nucleosides of MECA and NECA analogues was synthesized in good yield starting from (+/-) 6-azabicyclo[3.2.0]heptan-7-one.

A novel approach for the virtual screening and rational design of anticancer compounds.

A topological substructural approach to molecular design (TOSS-MODE) has been introduced for the selection and design of anticancer compounds. A quantitative model that discriminates anticancer compounds from the inactive ones in a training series was obtained. This model permits the correct classification of 91.43% of compounds in an external prediction set with only 1.43% of false actives and 7. 14% of false inactives. The model developed is then used in a simulation of a virtual search for Ras FTase inhibitors; 87% of the Ras FTase inhibitors used in this simulated search were correctly classified, thus indicating the ability of the TOSS-MODE model of finding lead compounds with novel structures and mechanism of action. Finally, a series of carbonucleosides was designed, and the compounds were classified as active/inactive anticancer compounds by using the model developed here. From the compounds so-designed, 20 were synthesized and evaluated experimentally for their antitumor effects on the proliferation of murine leukemia cells (L1210/0) and human T-lymphocyte cells (Molt4/C8 and CEM/0); 80% of these compounds were well-classified, as active or inactive, and only two pairs of isomeric compounds were false actives. The chloropurine derivatives were the most active compounds, especially compounds 6c, d.

Design, synthesis, conformational analysis and biological activities of purine-based 1,2-di-substituted carbocyclic nucleosides.

New 1,2-di-substituted carbocyclic nucleosides with 6-chloropurine, adenine and hypoxanthine bases were synthesized by construction of purine on the primary amino group of (+/-)-trans-2-aminocyclopentylmethanol. AM1 calculations showed close correspondence between the positions of the heteroatoms in the adenine derivative and dideoxyadenosine. The most active of the new compounds in antiviral assays and antitumoral assays against L1210/0, MOLT4/C8 and CEM/0 cells was the 6-chloropurine derivative.

New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction, and antiproliferative activity.

The synthesis of new tetrahydrobenzo- and benzopsoralen derivatives carrying at position 5 or 8 of the furocoumarin moiety a methoxy, hydroxy, or dimethylaminopropoxy side chain is reported. The study of their photoantiproliferative activity and ability to induce erythema on guinea pig skin allows us to state that the derivatives carrying the dimethylaminopropoxy side chain exhibit a very interesting photobiological pattern. Indeed, if compared with the lead compounds 5-MOP and 8-MOP, they exert a higher cytotoxic activity devoid of significant skin phototoxicity. Between them, the more interesting appears to be 16, a nonphototoxic compound whose antiproliferative activity on HeLa cells is 2 orders of magnitude higher than that of the reference drug 8-MOP. Photoreaction experiments have revealed that, like classic furocoumarins, A-T is the preferred nucleic base pair in its photobinding. Moreover, the extent of covalent photoaddition to DNA correlates well with the photobiological activity. For this compound a certain effect was also observed in the dark. Evaluation of the ability to induce DNA cleavage in the presence of human topoisomerase II has suggested that this enzyme is probably the target accountable for this effect.

Synthesis and biological evaluation of 1,2-disubstituted carbonucleosides of 6-substituted purine and 8-azapurine.

A series of new one two substituted carbonucleoside analogues (OTC), with the purine and 8-azapurine base linked through a methylene group at the cyclopentane ring, were synthesized and evaluated for their activity against a number of viruses and tumor cells in vitro.

AM1 theoretical study, synthesis and biological evaluation of some benzofuran analogues of anti-inflammatory arylalkanoic acids.

Using the semi-empirical quantum-mechanical method AM1, the molecular geometries of the arylalkanoic acids, indomethacin, naproxen and ibuprofen, were optimized and their frontier orbital charge distributions evaluated. Then, these molecular parameters were compared in order to identify structure-activity relationships and, on the basis of these, four benzofuran-3-acetic acids were designed as potential non-steroidal anti-inflammatory agents, and rapidly synthesized by a novel and easily generalized route. Notwithstanding the structural similarities between the synthesized compounds and the anti-inflammatory arylalkanoic acids, these compounds did not appreciably inhibit human platelet cyclooxygenase in vitro.

Synthesis and biological evaluation of 1,2-disubstituted carbonucleosides of 2-amino-6-substituted purine and 8-azapurine.

One, two-disubstituted carbocyclic nucleoside analogues bearing a 2-amino-6-substituted (chloro, hydroxy or amino) purine or 8-azapurine base were prepared by constructing the base about (+/-)-2-aminocyclopentane methanol, and their activities against a selection of viruses and tumor cells were determined in vitro.

Synthesis and mass spectrometric behavior of some new nucleosides as potential anti-HIV agents.

The electron-impact (EI) mass spectrometric behaviour of a series of 8-aza-purines derivatized with hydroxymethylcyclopentane and exhibiting cis-trans isomerization in the cyclopentane ring has been studied in detail with the aid of metastable-ion data. Specific fragmentation processes, present in both EI and mass analysed ion kinetic energy spectra of molecular species, allow characterization of the different pairs of stereoisomers. Contrary to what is observed in the case of purine analogs, the presence of a nitrogen atom in position 8 strongly inhibits fragmentation processes related to the heterocycle.

Synthesis and cytostatic activity of some sulfamido-anthraquinones.

N-1- or 2-anthraquinonyl derivatives of p-methyl-, p-methoxy- and p-aminobenzenesulfonamides were synthesized and evaluated in vitro as antitumour agents. Only N-(1-anthraquinonyl)-p-methylbenzenesulfonamide (1) and -p-methoxy benzene sulfonamide derivatives 3 and 4 showed slight antitumour activity.