Fluorinated Nucleosides: Synthesis and Biological Implication

A class of polycyclic compounds of general formula (II), of general formula (II'), or of general formula (II"), wherein Base 1 , Base 2 , Y, Y a , X a , X a1 , X b , X b1 , X c , X c1 , X d , X d1 , R 1 , R 1a , R 2 , R 2a , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.

Cyclic di-nucleotide compounds as sting agonists

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 syn...

6-(Het)aryl-7-deazapurine ribonucleosides as novel potent cytostatic agents.

7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five-membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base-pairing in DNA or RNA or better binding to enzymes. Several types of 7-deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7-hetaryl-7-deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6-hetaryl-7-deazapurine and thieno-fused deazapurine ribonucleosides, is not yet known. Many 7-deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar-modified derivatives of 7-deazapurine nucleosides are also strong antivirals. Most important are 2'-C-methylribo- or 2'-C-methyl-2'-fluororibonucleosides with anti-HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/med.21465

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

7-Functionalized 7-deazapurine β-d and β-l-ribonucleosides related to tubercidin and 7-deazainosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d or β-l-ribofuranose

The electrophilic fluorination of 4‐chloropyrrolo[2,3‐d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4‐chloro‐5‐fluoropyrrolo[2,3‐d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4‐chloro‐5,6‐dihydro‐5‐fluoro‐6‐hydroxypyrrolo[2,3‐d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5‐H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra‐O‐acetylribose gave 4‐chloro‐5‐fluoro‐7‐(2,3,5,‐tri‐O‐benzoyl‐β‐d‐ribofuranosyl)pyrrolo[2,3‐d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5‐fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh‐7 liver cells, normal mouse spleen cells stimulated with Con A (a T‐cell mitogen), and normal mouse spleen stimulated with LPS (a B‐cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observ...

Synthesis and biological activity of 5-fluorotubercidin.

The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.

Antibacterial 6'-n-modified 4,5-substituted aminoglycoside analogs

Antibacterial 4,6-substituted 6', 6'' and 1 modified aminoglycoside analogs

5-fluoro-pyrrolo[2,3-d]pyrimidine and 5-fluoro-pyrrolo[2,3-d]pyrimidine nucleoside compounds and methods for their preparation are disclosed.

METHODS FOR THE PREPARATION OF 5-FLUORO-PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS

The electrophilic fluorination of 4-chloropyrrolo[2,3-d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4-chloro-5,6dihydro-5-fluoro-6-hydroxypyrrolo[2,3-d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by H NMR and F NMR, and the 5-H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra-O-acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-Obenzoyl-b-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5-fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observed against L-1210 cells and toxicity in fibroblast cells was reduced.

Xiaojing Wang

Papers

Synthesis and biological activity of 5-fluorotubercidin.

Antibacterial 6'-n-modified 4,5-substituted aminoglycoside analogs

Antibacterial 4,6-substituted 6', 6'' and 1 modified aminoglycoside analogs

METHODS FOR THE PREPARATION OF 5-FLUORO-PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS

Nucleosides, Nucleotides and Nucleic Acids