Adenosine deaminase inhibitors. Synthesis and biological evaluation of (+/-)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d] [1,3]diazepin-8-ol and some selected C-5 homologues of pentostatin.

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Showalter HD, Putt SR, Borondy PE, Shillis JL

J Med Chem. 1983 Oct;26(10):1478-82.

PubMed ID

6604819 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pentostatin	Adenosine deaminase	Ki (nM)	0.0025	N/A	N/A	Details