A series of novel 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.
- MeSH
- Antineoplastic Agents pharmacology chemical synthesis chemistry MeSH
- Cell Cycle drug effects MeSH
- Cytostatic Agents pharmacology chemical synthesis chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Purines pharmacology chemical synthesis chemistry MeSH
- Ribonucleosides pharmacology chemical synthesis chemistry MeSH
- Stereoisomerism MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Antiviral Agents chemistry toxicity MeSH
- Cytogenetics drug effects MeSH
- Rats MeSH
- Humans MeSH
- Nucleotides analogs & derivatives MeSH
- Fetus drug effects MeSH
- Purines MeSH
- Teratogens MeSH
- Fetal Development MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Comparative Study MeSH
