Synthesis of a 3′-C-ethynyl-β-d-ribofuranose purine nucleoside library: Discovery of C7-deazapurine analogs as potent antiproliferative nucleosides

Abstract

A focused nucleoside library was constructed around a 3'-C-ethynyl-d-ribofuranose sugar scaffold, which was coupled to variously modified purine nucleobases. The resulting nucleosides were probed for their ability to inhibit tumor cell proliferation, as well as for their activity against a panel of relevant human viruses. While C6-aryl substituted purine nucleosides were found to be weakly active, several C7-substituted 7-deazapurine nucleosides elicited potent antiproliferative activity. Their activity spectrum was evaluated in the NCI-60 tumor cell line panel indicating activity against several solid tumor derived cell lines. Analog 32, equipped with a 7-deaza 7-chloro-6-amino-purin-9-yl base was evaluated in a metastatic breast tumor (MDA-MB-231-LM2) xenograft model. It inhibited both tumor growth and reduced the formation of lung metastases as revealed by BLI analysis. The dideazanucleoside analog 66 showed interesting activity against hCMV. These results highlight the potential advantages of recombining known sugar and nucleobase motifs as a library design strategy to discover novel antiviral or antitumor agents.

Discovery of Pyrrolo[2,3-b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma cruzi Agents

“…Halogen-containing heterocycles were obtained by electrophilic halogenation at the C3 position of 4-chloro-1 H -pyrrolo­[2,3- b ]­pyridine or C4-azido analogue 41 with the appropriate N -halosuccinimide or Selectfluor. To circumvent issues with the transformation of the 4-chlorine into an amino functionality at the nucleoside stage (also see Scheme ), due to the inherently higher electron density in the pyrrolo­[2,3- b ]­pyridine ring as compared to the pyrrolo­[2,3- d ]­pyrimidine system found in 7-deazapurine nucleoside analogues, it was decided to introduce an azido functionality before the glycosylation step (vide supra) as an amino group precursor. Azidation was effected under acidic conditions , because initial attempts with sodium azide alone or in the presence of 15-crown-5 failed to deliver any appreciable amounts of 41 (data not shown).…”

N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents

“…Human metastatic breast cancer xenografts were established as previously described [16]. The luciferasepositive LM2 lung metastatic cell line (MDA-MB-231 clone 4715) was a kind gift of Prof. Massagué [17].…”

Synthesis and evaluation of pharmacological activities of some 3-O-benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-D-ribofuranose derivatives as potential anti-inflammatory agents and analgesics

“…Chemically modified small interfering RNAs (siRNAs) containing ribofuranose sugar moiety in the 3’-overhang region seemed to have increased nuclease resistance and knockdown effect generating great interest in the field of RNA interference-based therapeutics ( 11 ). Ribofuranose nucleosides also exhibited cytotoxic activity in different cell lines ( 12 ) as well as antiproliferative activity in both molecular docking study and solid tumor- derived cell lines ( 13 14 ). Chemo-enzymatically synthesized ribofuranose derived cationic surfactants and ribofuranose derivatives of 1,5- benzothiazepines have been reported to have good antimicrobial activity ( 15 16 ).…”