Kim C H, Marquez V E, Mao D T, Haines D R, McCormack J J
J Med Chem. 1986 Aug;29(8):1374-80. 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.
将四氢尿苷（THU，2）和饱和的2-氧代-1,3-二氮杂环庚烷核苷用作口服胞苷脱氨酶（CDA）抑制剂时遇到的问题之一是它们的酸不稳定性。在酸性条件下，这些化合物会迅速转化为无活性的吡喃核糖苷形式。为了解决这个问题，人们尝试对酸稳定但活性较低的CDA抑制剂1-β-D-呋喃核糖基-2(1H)-嘧啶酮（1）进行官能化，以期将其活性提高到THU所达到的水平。基于过渡态（TS）概念，选择在C-4位引入羟甲基取代基，从而合成了4-(羟甲基)-1-β-D-呋喃核糖基-2(1H)-嘧啶酮（10）、3,4-二氢-4-(羟甲基)-1-β-D-呋喃核糖基-2(1H)-嘧啶酮（7）和3,4,5,6-四氢-4-(二羟甲基)-1-β-D-呋喃核糖基-2(1H)-嘧啶酮（28）。关键的中间体前体4-[(苯甲酰氧基)甲基]-1-(2,3,5-三-O-苯甲酰基-β-D-呋喃核糖基)-2(H)-嘧啶酮（24）是通过2-甲氧基-4-[(苯甲酰氧基)甲基]嘧啶（20）与2,3,5-三-O-苯甲酰基-1-D-呋喃核糖基溴（21）之间的经典希尔伯特-约翰逊反应得到的。24脱保护得到化合物10，而其硼氢化钠还原产物在去除保护基后得到化合物7和28。缺乏羟甲基取代基的3,4-二氢-1-β-D-呋喃核糖基-2(1H)-嘧啶酮（9）和3,6-二氢-1-β-D-呋喃核糖基-2(1H)-嘧啶酮（8）的合成也采用了类似的方法。带有羟甲基取代基的新化合物比THU更耐酸，并且它们对CDA的抑制活性（以Ki值表示）在10^(-4)至10^(-7) M范围内，符合TS理论。特别是，当针对小鼠肾脏CDA进行检测时，化合物7优于其母体化合物1，且与THU具有同等效力（Ki = 4×10^(-7) M）。该化合物优异的酸稳定性及其对CDA的强效抑制特性，应为测试快速脱氨药物（如阿糖胞苷）的口服组合提供一种方法，而不会出现与THU酸不稳定性相关的并发症。
