Folate analogues. 31. Synthesis of the reduced derivatives of 11-deazahomofolic acid, 10-methyl-11-deazahomofolic acid, and their evaluation as inhibitors of glycinamide ribonucleotide formyltransferase.
Folate analogues. 31. Synthesis of the reduced derivatives of 11-deazahomofolic acid, 10-methyl-11-deazahomofolic acid, and their evaluation as inhibitors of glycinamide ribonucleotide formyltransferase.
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叶酸类似物。
DOI：
10.1021/jm00126a022
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发表时间：
1989
影响因子：
7.3
通讯作者：
Edelstein,MP
中科院分区：
文献类型：
--
作者：
Nair,MG;Murthy,BR;Patil,SD;Kisliuk,RL;Thorndike,J;Gaumont,Y;Ferone,R;Duch,DS;Edelstein,MP
Boon-Leigh程序，包括6-氯-5-硝基嘧啶（22）与氨基酮（20或21）缩合，然后还原硝基，环化和L-谷氨酰化，导致形成11-脱氮高叶酸（29）及其10-甲基衍生物（30）。通过催化氢化制备了相应的（6 R，S）-5，6，7，8-四氢（4，5）和7，8-二氢（31，32）衍生物。（6S）-11-脱氮四氢高甲酸酯由29通过酶促还原制备。化合物29和30对干酪乳杆菌甘氨酰胺核糖核苷酸（GAR）甲酰基转移酶几乎没有影响（IC 50> 2 × 10 - 6 M），但（6 R，S）-11-脱氮四氢高叶酸（4）是该酶的有效抑制剂（ICM= 5 × 10 - 8 M）。其抑制性比33（6S化合物）高至少100倍，表明在C6（34）处具有非天然构型的混合物的6 R组分负责有效抑制。化合物4是鼠（L1210）和人（M0 LT-4）白血病细胞GAR甲酰基转移酶的弱得多的抑制剂（IC> 1 X 10 - 5 M）。(6fi S）-11-脱氮-10-甲基四氢高叶酸（5）（IC 50 = LI
The Boon-Leigh procedure, involving condensation of a 6-chloro-5-nitropyrimidine (22) with an-amino ketone (20 or 21) followed by reduction of the nitro group, cyclization, and L-glutamylation, led to the formation of 11-deazahomofolate (29) and its 10-methyl derivative (30). The corresponding (6fi, S)-5, 6, 7, 8-tetrahydro (4, 5) and 7, 8-dihydro (31, 32) derivatives were prepared by catalytic hydrogenation.(6S)-11-Deazatetrahydrohomofoíate was prepared from 29 by enzymatic reduction. Compounds 29 and 30 had little effect (IC50> 2 X 10" 6 M) on Lactobacillus casei glycinamide ribonucleotide (GAR) formyltransferase but (6R, S)-ll-deazatetrahydrohomofolate (4) is a potent inhibitor of this enzyme (ICM= 5 X 10 “8 M). It is at least 100 times more inhibitory than 33, the 6S compound, indicating that the 6R component of the mixture having the unnatural configuration at C6 (34) is responsible for the potent inhibition. Compound 4 is a much weaker inhibitor of murine (L1210) and human (MOLT-4) leukemia cell GAR formyltransferases (IC^> 1 X 10" 5 M).(6fi, S)-11-Deaza-10-methyltetrahydrohomofolate (5)(IC50= LI