Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity.
Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity.
复制标题
DOI：
10.1021/jm8003366
复制
发表时间：
2008-08-28
影响因子：
7.3
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Deng Y;Wang Y;Cherian C;Hou Z;Buck SA;Matherly LH;Gangjee A
以4-甲酰基苯甲酸甲酯为起始原料，与三苯基溴化磷发生Wittig反应，经还原转化为α-溴甲基酮，合成了一系列6-取代吡咯并[2，3-d]嘧啶类叶酸拮抗剂（化合物2、3、4和5）。2，4-二氨基-4-氧代嘧啶与α-溴代酮环合，与L-谷氨酸二乙酯偶联，皂化得到2-5。化合物2-5对RFC具有可忽略的底物活性，但对表达FRα或FRβ的中国仓鼠卵巢细胞以及对表达FRα的KB和IGROV 1人肿瘤细胞显示出强效（纳摩尔）和选择性抑制活性。还观察到KB细胞集落形成的抑制。甘氨酰胺核糖核苷酸甲酰转移酶（GARFT酶）被确定为吡咯并[2，3-d]嘧啶的主要细胞内靶点。选择性FR靶向、缺乏RFC转运和GARFT酶抑制的组合性质导致有效的抗肿瘤活性是前所未有的，并且保证了这些类似物作为抗肿瘤剂的开发。
A series of 6-substituted classical pyrrolo[2,3-d]pyrimidine antifolates with a 3- to 6-carbon bridge between the heterocycle and the benzoyl-L-glutamate (compounds 2, 3, 4 and 5, respectively) was synthesized starting from methyl 4-formylbenzoate and a Wittig reaction with the appropriate triphenylphosphonium bromide, followed by reduction and conversion to the α-bromomethylketones. Cyclocondensation of 2,4-diamino-4-oxopyrimidine with the α-bromoketones, coupling with diethyl-L-glutamate and saponification afforded 2–5. Compounds 2–5 had negligible substrate activity for RFC but showed variably potent (nanomolar) and selective inhibitory activities toward Chinese hamster ovary cells that expressed FRα or FRβ, and toward FRα-expressing KB and IGROV1 human tumor cells. Inhibition of KB cell colony formation was also observed. Glycinamide ribonucleotide formyl transferase (GARFTase) was identified as the primary intracellular target of the pyrrolo[2,3-d]pyrimidines. The combined properties of selective FR targeting, lack of RFC transport, and GARFTase inhibition resulting in potent antitumor activity are unprecedented and warrant development of these analogs as antitumor agents.
登录
查看更多内容
影响因子：
7.3
作者：
Gangjee, A;Zeng, YB;Kisliuk, RL
通讯作者：
Kisliuk, RL
影响因子：
3.5
作者：
Gangjee, Aleem;Yang, Jie;Kisliuk, Roy L.
通讯作者：
Kisliuk, Roy L.
影响因子：
64.5
作者：
Qiu, Andong;Jansen, Michaela;Goldman, I. David
通讯作者：
Goldman, I. David
影响因子：
11.5
作者：
Chattopadhyay, S;Wang, YH;Goldman, ID
通讯作者：
Goldman, ID
影响因子：
2.9
作者：
Sanghani, SP;Moran, RG
通讯作者：
Moran, RG