Synthesis, Cytostatic, Antimicrobial, and Anti-HCV Activity of 6‑Substituted 7‑(Het)aryl-7-deazapurine Ribonucleosides

A series of 80 7-(het)­aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)­aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against <i>Mycobacterium bovi</i>s and also against hepatitis C virus in a replicon assay

Novel 5‑Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Bruton’s tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly B-cells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53–/–), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, possessing free binding energies of −10.8, −11.1, −11.3, and −10.8 kcal/mol, respectively, and displaying selective cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated the antiproliferative activity of 9h in RAMOS cells through selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk, upstream proteins in the BCR signaling pathway. In conclusion, we identified a promising oxindole derivative (9h) that shows specificity in modulating BTK signaling pathways

Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7‑Deazapurine Ribonucleosides

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno­[2′,3′:4,5]­pyrrolo­[2,3-<i>d</i>]­pyrimidines and thieno­[3′,2′:4,5]­pyrrolo­[2,3-<i>d</i>]­pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts

Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7‑Substituted 7‑(Het)aryl-7-deazaadenine Ribonucleosides

Adenosine kinase (ADK) from <i>Mycobacterium tuberculosis</i> (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)­aryl-7-deazaadenine ribonucleosides with Mtb and human (<i>h</i>) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and <i>h</i>ADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D ¹H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of <i>h</i>ADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites