Publications

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

9-(3-Deoxy-β-D-erythro-pentofuranosyl)-2,6-diaminopurine (6) was synthesized by an enzymatic transglycosylation of 2,6-diaminopurine (2) with 3′-deoxycytidine (1) as a donor of 3-deoxy-D-erythro-pentofuranose moiety. This transformation comprises i) deamination of 1 to 3′-deoxyuridine (3) under the action of whole cell (E. coli BM-11) cytidine deaminase (CDase), ii) the phosphorolytic cleavage of 3 by uridine phosphorylase (UPase) giving rise to the formation of uracil (4) and 3-deoxy-α-D-erythro-pentofuranose-1-O-phosphate (5), and iii) coupling of the latter with 2 catalyzed by whole cell (E. coli BMT-4D/1A) purine nucleoside phosphorylase (PNPase). Deamination of 6 by adenosine deaminase (ADase) gave 3′-deoxyguanosine (7). Treatment of 6 with NaNO2 afforded 9-(3-deoxy-β-D-erythro-pentofuranosyl)-2-amino-6-oxopurine (3′-deoxyisoguanosine; 8). Schiemann reaction of 6 (HF/HBF4+NaNO2) gave 9-(3-deoxy-β-D-erythro-pentofuranosyl)-2-fluoroadenine (9).

A series of novel dihydro-alkyloxy-benzyl-oxopyrimidine derivatives were synthesized and evaluated for their activity against influenza virus in Madin-Darby canine kidney cells. Four dihydro-alkyloxy-benzyl-oxopyrimidine derivatives (4a1, 4a2, 4a3, and 4d1) showed potent activity against influenza virus. Among them, compound 4a3 was the most promising lead with broad activity against influenza A (antiviral EC(50) values of 9 and 18 μm for the A/H1N1 and A/H3N2 subtype, respectively) and influenza B viruses (EC(50) : 33 μm). The antiviral mechanism of action of these dihydro-alkyloxy-benzyl-oxopyrimidine derivatives must be quite different from that of the currently approved anti-influenza virus drugs that target the viral M2 or neuraminidase proteins. The dihydro-alkyloxy-benzyl-oxopyrimidine derivatives represent a new avenue for further optimization and development of novel anti-influenza virus agents.

As novel anti-HIV agents, the G-tetrad-forming oligonucleotides have been explored for their structure-activity relations with regard to inhibition of integrase (IN) (N. Jing, Expert Opin. Investig. Drugs (2000) 9, 1777-1785). We have now developed two families of G-quartet oligonucleotides: T40217-T40222, with potential formation of a tail-to-tail G-quartet dimer, and T40224-T40227, with phosphorothioate (PT) linkages in the guanine loops. The results obtained from biophysical measurements and the assays of the inhibition of HIV-1 IN and virus replication demonstrated that an increase in the length of the G-quartet structure from a monomer (15A) to a tail-to-tail dimer (47A) does not distinctly disrupt the inhibition of HIV-1 IN activity or the inhibition of HIV-1 replication in cell cultures. G-quartet oligonucleotides were observed to induce molecular aggregation of HIV-1 IN and interrupt the binding of viral DNA to HIV-1 IN. Also, PT substitutions did not confer any advantages compared with the regular phosphodiesters for the inhibition of HIV-1 replication by intramolecular G-quartets. The G-quartet motif is the primary requirement for the remarkable nuclease resistance and pronounced biological efficacy of these oligonucleotides.

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 4-6), 8-azapurine (7 and 8) or uridine (9) base on the amino group of (1S,3R)-3-amino-2,2,3-trimethylcyclopentylmethanol (10). At subtoxic concentrations, compounds 5-9 showed at best marginal antiviral activity.