Synthesis, chemical and enzymatic hydrolysis, and aqueous solubility of amino acid ester prodrugs of 3-carboranyl thymidine analogs for boron neutron capture therapy of brain tumors.
Synthesis, chemical and enzymatic hydrolysis, and aqueous solubility of amino acid ester prodrugs of 3-carboranyl thymidine analogs for boron neutron capture therapy of brain tumors.
复制标题
用于脑肿瘤硼中子捕获治疗的 3-碳硼基胸苷类似物的氨基酸酯前药的合成、化学和酶水解以及水溶性。
DOI：
10.1016/j.ejmech.2012.07.033
复制
发表时间：
2012
影响因子：
6.7
通讯作者：
Tjarks,Werner
中科院分区：
文献类型：
--
作者：
Hasabelnaby,Sherifa;Goudah,Ayman;Agarwal,HiteshK;abdAlla,MosaadSM;Tjarks,Werner
针对脑肿瘤亲体化合物水溶性不足的问题，合成了两种3-Carboranyl胸苷类似物(3-CTA)的水溶性前药L-缬氨酸、L-谷氨酸和甘氨酸酯，命名为N5和N5-2OH，用于脑肿瘤的硼中子俘获治疗。制备氨基酸酯类前药，并以盐酸盐形式储存。这些氨基酸酯前药在pH 5、pH 6和pH 7.4的磷酸盐缓冲盐水(PBS)中的溶解度比亲本N5和N5-2OH提高了48-6600倍。在pH为7.4的PBS、牛血清和牛脑脊液中评价氨基酸酯类前药的稳定性。在所有三种培养介质中的水解率主要取决于氨基酸的促进作用，其次取决于3-CTA脱氧核糖部分的酯化位置。总体而言，3‘-氨基酸酯类前药对化学和酶促水解的敏感性低于5’-氨基酸酯类前药，后者的稳定性由高到低依次为：5‘-缬氨酸、5’-谷氨酸和5‘-甘氨酸。5‘-氨基酸酯类前药在牛脑脊液中的水解率总体上高于PBS，略低于牛血清。总体而言，N5的5‘-谷氨酸酯前药和N5和N5-2OH的5’-甘氨酸酯前药似乎是最有希望进行临床前BNCT研究的候选药物。
Various water-soluble l-valine-, l-glutamate-, and glycine ester prodrugs of two 3-Carboranyl Thymidine Analogs (3-CTAs), designated N5 and N5-2OH, were synthesized for Boron Neutron Capture Therapy (BNCT) of brain tumors since the water solubilities of the parental compounds proved to be insufficient in preclinical studies. The amino acid ester prodrugs were prepared and stored as hydrochloride salts. The water solubilities of these amino acid ester prodrugs, evaluated in phosphate buffered saline (PBS) at pH 5, pH 6 and pH 7.4, improved 48–6600 times compared with parental N5 and N5-2OH. The stability of the amino acid ester prodrugs was evaluated in PBS at pH 7.4, Bovine serum, and Bovine cerebrospinal fluid (CSF). The rate of the hydrolysis in all three incubation media depended primarily on the amino acid promoiety and, to a lesser extend, on the site of esterification at the deoxyribose portion of the 3-CTAs. In general, 3′-amino acid ester prodrugs were less sensitive to chemical and enzymatic hydrolysis than 5′-amino acid ester prodrugs and the stabilities of the latter decreased in the following order: 5′-valine > 5′-glutamate > 5′-glycine. The rate of the hydrolysis of the 5′-amino acid ester prodrugs in Bovine CSF was overall higher than in PBS and somewhat lower than in Bovine serum. Overall, 5′-glutamate ester prodrug of N5 and the 5′-glycine ester prodrugs of N5 and N5-2OH appeared to be the most promising candidates for preclinical BNCT studies.
登录
查看更多内容
5-(碳硼烷基烷基巯基)-2-脱氧尿苷和 3-(碳硼烷基烷基)胸苷的合成及其作为人胸苷激酶 1 和 2 底物的评估。
DOI：
10.1021/jm990125i
发表时间：
1999
期刊：
Journal of medicinal chemistry.
影响因子：
--
作者：
Lunato,AJ;Wang,J;Woollard,JE;Anisuzzaman,AK;Ji,W;Rong,FG;Ikeda,S;Soloway,AH;Eriksson,S;Ives,DH;Blue,TE;Tjarks,W
通讯作者：
Tjarks,W
影响因子：
2.7
作者：
Keisuke Yamamoto;Yasuyuki Endo
通讯作者：
Yasuyuki Endo
肠道二肽/三肽转运蛋白 PepT1 的嘌呤和嘧啶类似物的前药：Caco-2 细胞中 hPepT1 的亲和力、水介质中的药物释放和体外代谢。
DOI：
10.1016/s0168-3659(02)00413-3
发表时间：
2003
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
A. E. Thomsen;G. Friedrichsen;Arne Hagsten Sørensen;R. Andersen;C. Nielsen;B. Brodin;M. Begtrup;S. Frokjaer;B. Steffansen
通讯作者：
B. Steffansen
亲水性增强的 3-碳硼烷基胸苷类似物 (3CTA)，用于癌症的硼中子捕获疗法 (BNCT)。
影响因子：
3.5
作者：
Sureshbabu Narayanasamy;B. Thirumamagal;Jayaseharan Johnsamuel;Youngjoo Byun;A. S. Al;E. Usova;Guirec Y. Cosquer;Junhua Yan;A. Bandyopadhyaya;R. Tiwari;S. Eriksson;W. Tjarks
通讯作者：
W. Tjarks
影响因子：
11.2
作者：
Al-Madhoun, AS;Johnsamuel, J;Eriksson, S
通讯作者：
Eriksson, S