Synthesis of pyrimidin-2-one nucleosides as acid-stable inhibitors of cytidine deaminase

• Published in: Journal of medicinal chemistry Vol. 29; no. 8; pp. 1374 - 1380
• Main Authors: Kim, Chong Ho, Marquez, Victor E, Mao, David T, Haines, David R, McCormack, John J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1986
• Subjects: Adenosine Deaminase Inhibitors; Animals; Carbohydrates. Nucleosides and nucleotides; Chemistry; Cytidine Deaminase - antagonists & inhibitors; Exact sciences and technology; Kidney - enzymology; Magnetic Resonance Spectroscopy; Mice; Nucleoside Deaminases - antagonists & inhibitors; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Pyrimidine Nucleosides - chemical synthesis; Pyrimidinones - chemical synthesis; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Tetrahydrouridine - pharmacology; Enzyme inhibitor; Ureas; Infrared spectrum; Ribonucleoside; NMR spectrum; Pyrimidine nucleoside; Biological activity; Cytidine deaminase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00158a009

One of the problems encountered in the use of tetrahydrouridine (THU, 2) and saturated 2-oxo-1,3-diazepine nucleosides as orally administered cytidine deaminase (CDA) inhibitors is their acid instability. Under acid conditions these compounds are rapidly converted into inactive ribopyranoside forms. A solution this problem was sought by functionalizing the acid-stable but less potent CDA inhibitor 1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (1) with the hope of increasing its potency to the level achieved with THU. The selection of the hydroxymethyl substituent at C-4, which led to the synthesis of 4-(hydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (10), 3,4-dihydro-4-(hydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (7), and 3,4,5,6-tetrahydro-4-(dihydroxymethyl)-1-beta-D-ribofuranosyl-2(1H)-p yrimidinone (28) was based on the transition-state (TS) concept. The key intermediate precursor, 4-[(benzoyloxy)methyl]-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-2(H) -pyrimidinone (24), was obtained via the classical Hilbert-Johnson reaction between 2-methoxy-4-[(benzoyloxy)methyl]pyrimidine (20) and 2,3,5-tri-O-benzoyl-1-D-ribofuranosyl bromide (21). Deprotection of 24 afforded compound 10, while its sodium borohydride reduction products afforded compounds 7 and 28 after removal of the blocking groups. Syntheses of 3,4-dihydro-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (9) and 3,6-dihydro-1-beta-D-ribofuranosyl-2(1H)-pyrimidinone (8), which lack the hydroxymethyl substituent, was accomplished in a similar fashion. The new compounds bearing the hydroxymethyl substituent were more acid stable than THU, and their CDA inhibitory potency, expressed in terms of Ki values, spanned from 10(-4) to 10(-7) M in a manner consistent with the TS theory. Compound 7, in particular, was superior to its parent 1 and equipotent to THU (Ki = 4 X 10(-7) M) when examined against mouse kidney CDA. The superior acid stability of this compound coupled to its potent inhibitory properties against CDA should provide a means of testing oral combinations of rapidly deaminated drugs, viz. ara-C, without the complications associated with the acid instability of THU.