Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides

Abstract

Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.

N‐(Indazolyl)benzamido Derivatives as CDK1 Inhibitors: Design, Synthesis, Biological Activity, and Molecular Docking Studies

“…The displacement from the 3-position of the indazole nucleus to the 5-and 6-positions (compounds 11m and 13m), the substitution of the benzamido moiety with the phenoxyacetamido and phenylacetamido ones (compounds 16 and 17), and the amidic function inversion (compounds 23 and 24) gave rise to inactive or scarcely active compounds. To rationalize the SAR observed for N-(indazolyl)benzamido derivatives, compounds 9a -o, 11m, 13m, 16,17,23, and 24 were docked into the human thr160-phospho cdk2 / cyclin A (1H1S) together with the reference inhibitor purvanalol A. Comparison of the different docking results of the most active compounds 9e, f, i -n, and purvanalol A 3 shows that, in principle, they adopt the same binding mode in the ATPbinding cleft (Fig.…”

“…Structures of the designed derivatives 9a -o, 11m, 13m, 16,17,23, and 24 were generated by molecular modelling with Cerius 2 4.10 software by optimizing their geometry using the Dreiding 2.21 force field with Gasteiger charges.…”

“…The CDK1 inhibitory activity for derivatives 9a -o, 11m, 13m, 16,17,23, and 24 was determined in-house in a nonradioisotopic assay (CycLex Cdc2-Cyclin B kinase assay kit) using purvanolol A as reference compound. The results as percent of CDK inhibition at 10 lM concentration are reported in Table 1.…”

“…Compounds 9a -o, 11m, 13m, 16,17,23, and 24 were tested in vitro for antiproliferative activity against K562 (human chronic myelogenous leukemia) cell line. These cell lines were grown at 378C in a humidified atmosphere containing 5% CO 2 , in RPMI-1640 medium supplemented with 10% fetal bovine serum and antibiotics.…”

“…A comparison of the Connolly surfaces of 9a, purvanalol A and the most active compounds 9c, f, in showed that the presence of the substituents in the positions 3 and 4 determines an increase of the surface in this region with respect to the unsubstituted 9a and, consequently, a greater number of positive hydrophobic interactions with Lys89, Asp86, and Gln85. Moreover, inactive (11m, 13m,17,23,24) and scarcely active (9a, b, c, g, n, o, 16) compounds adopt a binding mode different from purvanalol A (Fig. 6) and form one or no hydrogen bonds with the hinge region.…”