ABSTRACT
The synthesis of several analogues of (8R)-3-(2-deoxy-beta-D-erythro- pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin, 1a) is described. Ring closure of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (3) with triethyl orthoacetate or triethyl orthopropionate gave the C-5 methyl and ethyl ketoaglycons, 6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (4b) and 5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4c), respectively. Stannic chloride catalyzed condensation of the pertrimethylsilyl derivatives of 4b and 4c with a protected glycosyl halide afforded anomeric mixtures of ketonucleosides 3-(2-deoxy-3,5-di-O-p-toluoyl-beta- and -alpha-D-erythro-pentofuranosyl)-6,7-dihydro-5-methylimidazo[4,5-d] [1,3]diazepin-8(3H)-one (5b and 6b) and 3-(2-deoxy-3,5-di-O-p-toluoyl)-beta- and -alpha-D-erythro-pentofuranosyl)-5-ethyl-6,7-dihydroimidazo[4,5-d]- [1,3]diazepin-8(3H)-one (5c and 6c), respectively. Subsequent separation of the anomers, followed by deprotection and reduction of 5b, 6b, and 5c, afforded the respective 8R and 8S isomers. Stannic chloride catalyzed condensation of pertrimethylsilyl ketoaglycon 4a with 2-(chloromethoxy)-1-(p-toluoyloxy) ethane to give ketonucleoside 6,7-dihydro-3-[[2-(p-toluoyloxy)ethoxy] methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one (9a) was followed by deprotection to 6,7-dihydro-3[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3] diazepin-8(3H)-one (9b) and then reduction to the racemic acyclic pentostatin analogue (+/-)-3,6,7,8-tetrahydro-3-[ (2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol (2). Ki values for the in vitro adenosine deaminase (EC 3.5.4.4; type I; calf intestinal mucosa) inhibitory activities of 1b, 1c, and 2 were determined to be 1.6 X 10(-8), 1.5 X 10(-6), and 9.8 X 10(-8) M, respectively. When compounds 2 and 9b were tested in combination with vidarabine against herpes simplex virus, type 1, in an HEp-2 plaque reduction assay, only compound 2 was able to potentiate the antiviral activity of vidarabine.
Subject(s)
Adenosine Deaminase Inhibitors , Coformycin/chemical synthesis , Coformycin/pharmacology , Nucleoside Deaminases/antagonists & inhibitors , Ribonucleosides/chemical synthesis , Ribonucleosides/pharmacology , Animals , Coformycin/analogs & derivatives , Indicators and Reagents , Intestinal Mucosa/enzymology , Kinetics , Magnetic Resonance Spectroscopy , Pentostatin , Spectrophotometry , Structure-Activity RelationshipABSTRACT
Several nucleosides modified and chain extended at the 5'-position have been synthesized as follows: N6-benzamido- 9-(2,3-di-O-benzoyl-beta-D-arabino-pentodialdo-1,4-furanosyl)adenine, O=CHR, a leads to (E)-EtOCOCH=CHR (2) b leads to EtOCOCH2CH2R (3) c leads to H2NCOCH2CH2R (6) d leads to 1-(adenin-9- yl)-1,5,6-trideoxy-beta-D-arabino-hepto-1,4-furanuronamide (8); 3 e leads to ethyl 1-(adenin-9-yl)-1,5,6-trideoxy-beta-D-arabino-hepto-1, 4-furanuronate (5) f leads to 1-(adenin-9-yl)-1, 5,6-trideoxy-beta-D-arabino-hepto-1,4-furanuronic acid (4); 5 g leads to 9-(5,6-dideoxy-beta-D-arabino-hepto-1,4-furanosyl)adenine (7) [where a = EtOCOCH=PPh3; b = H2, Pd/C; c = Me2A1NH2; d = NH3/MeOH; e = NaOEt/EtOH; f = NaOH/MeOH; g = LiA1H4]. Both 7 and 8 show activity against herpes simplex virus type 1. The mechanism for such activity is unknown. Compounds 5 and 8 exhibited weak coronary vasodilation effects in dogs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Coronary Circulation/drug effects , Vidarabine/analogs & derivatives , Adenosine Deaminase/metabolism , Animals , Cattle , Cell Line , DNA Replication/drug effects , Dogs , Indicators and Reagents , Intestinal Mucosa/enzymology , Magnetic Resonance Spectroscopy , Simplexvirus/drug effects , Spectrophotometry , Structure-Activity Relationship , Vascular Resistance/drug effects , Vasodilation/drug effectsABSTRACT
A number of 2',3'- and 3',5'-di-O-acyl derivatives of 9-beta-D-arabinofuranosyladenine (1) were prepared and evaluated as antivirals. These compounds, designed as prodrugs of 1, offer a range of solubilities and lipophilicities, as well as a resistance to adenosine deaminase, that render some as being attractive as possibly useful antiviral agents. Of particular note is 9-(2,3-di-O-acetyl-beta-D-arabinofuranosyl)adenine that was found to be effective as a topical agent in a guinea pig model of genital herpes.
Subject(s)
Vidarabine/analogs & derivatives , Animals , Antiviral Agents/chemical synthesis , Chemical Phenomena , Chemistry , Female , Guinea Pigs , Herpes Simplex/drug therapy , Simplexvirus/drug effects , Vidarabine/chemical synthesis , Vidarabine/pharmacologyABSTRACT
A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.
