Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites.
Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites.
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叶酸和甲氨蝶呤的含氟谷氨酸类似物的生物学特性，其形成聚（γ-谷氨酸）代谢物的能力发生改变。
DOI：
10.1016/0006-2952(96)00485-6
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发表时间：
1996
影响因子：
5.8
通讯作者：
Coward,JK
中科院分区：
文献类型：
--
作者：
McGuire,JJ;Hart,BP;Haile,WH;Magee,KJ;Rhee,M;Bolanowska,WE;Russell,C;Galivan,J;Paul,B;Coward,JK
合成了含有氟谷氨酸的叶酸和甲氨蝶呤（MTX）类似物，改变了聚γ-谷氨酸（γ-谷氨酸）的代谢能力，以探讨聚谷氨酸的生物学作用。与叶酸相比，dl-e，t-γ-氟叶酸（一种不良的聚谷氨酰化底物）在促进叶酸缺失的H35大鼠肝癌细胞生长方面的效力要低约25倍。dl-β，β-二氟叶酸，一种比叶酸更容易形成二氟酸酯的化合物，其效力至少与叶酸相当。亚叶酸素（LV）是一种还原型叶酸，在促进生长方面的效力是叶酸的30倍，而类似形式的dl-e、t-γ-氟叶酸、dl-e、t-γ-氟叶酸（dl-e、t-γ-FLV）的效力仅是叶酸的4倍。LV和dl-e，t- γ-FLV都保护或“拯救”细胞免受MTX的生长抑制作用；然而，氟模拟物的浓度需要提高37至46倍。叶酸、dl-e、t-γ-氟叶酸、LV和dl-e、t-γ-FLV均增强了5-氟-2′-脱氧尿苷对CCRF-CEM人白血病细胞的生长抑制作用；再次需要更高浓度的氟化类似物。立体化学纯l-t-γ-氟甲氨蝶呤（l-t-γ-FMTX）是一种不良的多谷氨酰化底物，被评价为细胞生长抑制剂。在持续暴露中，l-t-γ-FMTX作为CCRF-CEM生长抑制剂的效力比MTX低7倍。这些氟化叶酸和MTX类似物的结果提供了深入了解谷氨酸代谢对这些生物学和药理学作用的重要性。
Fluoroglutamate-containing analogs of folates and methotrexate (MTX) with altered capacities for poly (γ-glutamate) metabolism were synthesized to probe the biological roles of polyglutamates. Compared to folic acid, dl-e,t-γ-fluorofolic acid, a compound that is a poor substrate for polyglutamylation, was ≈25-fold less potent in promoting growth of folate-depleted H35 rat hepatoma cells. dl-β,β-Difluorofolic acid, a compound that forms diglutamates more readily than does folic acid, was at least equivalent to folic acid in potency. Leucovorin (LV), a reduced folate, was 30-fold more potent than folic acid in promoting growth, whereas the analogous form of dl-e,t-γ-fluorofolate, dl-e,t-γ-fluoroleucovorin (dl-e,t-γ-FLV) was only 4-fold more potent than folic acid. Both LV and dl-e,t--γ-FLV protected or “rescued” cells from the growth inhibitory effects of MTX; however a 37- to 46-fold higher concentration of the fluoro analog was required. Folic acid, dl-e,t-γ-fluorofolic acid, LV, and dl-e,t-γ-FLV each potentiated the growth inhibitory effect of 5-fluoro-2′-deoxyuridine on CCRF-CEM human leukemia cells; higher concentrations of fluorinated analogs again were required. Stereochemically pure l-t-γ-fluoromethotrexate (l-t-γ-FMTX), a poor substrate for polyglutamylation, was evaluated as a cell growth inhibitor. In continuous exposure, l-t-γ-FMTX was 7-fold less potent than MTX as an inhibitor of CCRF-CEM growth. Results with these fluorinated folate and MTX analogs offer insight into the importance of polyglutamate metabolism to these biological and pharmacological effects.
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DOI：
10.7326/0003-4819-72-1-153_1
发表时间：
1969
期刊：
--
影响因子：
--
作者：
Raymond L. Blakley
通讯作者：
Raymond L. Blakley
合成高比活度氚化 (6S)-5-甲酰四氢叶酸的简单程序。
影响因子：
2.9
作者：
Moran,RG;Colman,PD
通讯作者：
Colman,PD
D,L-赤型和 D,L-苏型-γ-氟甲氨蝶呤与人白血病细胞二氢叶酸还原酶的相互作用。
影响因子：
5.8
作者：
McGuire,JJ;Haile,WH;Coward,JK
通讯作者：
Coward,JK
抗叶酸剂的化学和生物活性。
影响因子：
--
作者：
A. Rosowsky
通讯作者：
A. Rosowsky
DOI：
--
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Osborne,CB;Lowe,KE;Shane,B
通讯作者：
Shane,B