Temple C, Bennett L L, Rose J D, Elliott R D, Montgomery J A, Mangum J H
J Med Chem. 1982 Feb;25(2):161-6. doi: 10.1021/jm00344a014.
Reaction of 5,6,7,8-tetrahydrofolic acid (THF,7) with phosgene, thiophosgene, and cyanogen bromide gave the bridged derivatives, 5,10-(CO)-THF (8), 5,10-(CS)-THF (9), and 5,10-(C = NH)-THF (11), respectively. Catalytic hydrogenation of 10-(chloroacetyl)folic acid (2) gave 5,10-(CH2CO)-THF (12). A similar reaction with 10-(3-chloropropionyl)folic acid (3) gave 10-(ClCH2CH2CO)-THF (14) rather than 5,10-(CH2CH2CO)-THF (13). In the catalytic hydrogenation of 10-ethoxalylfolic acid (5), the initial product 10-(EtO2CCO)-THF (22) rearranged readily to give 5-(EtO2CCO)-THF (21). Acylation of THF with chloroacetyl chloride gave a N5,N10-diacylated product (18 or 19), which could not be converted to 5,10-COCH2)-THF (17). Reductive alkylation of THF with glyoxylic acid and 5-hydroxypentanal, respectively, gave 5-(HO2CCH2)-THF (24) and 5-[HO(CH2)5]-THF (25). Reductive dialkylation of THF with formaldehyde gave 5,10-(CH3)2-THF (27), whereas glyoxal gave 5,10-CH2CH2)-THF (10). Also, both folic acid and 5-(CHO)-THF were reductively alkylated with formaldehyde to give 10-methylfolic acid (6) and 5-(CHO)-10-(CH3)-THF (28), respectively. These compounds were tested as inhibitors of the enzymes involved in folate metabolism and for activity against lymphocytic leukemia P388 in mice.
5,6,7,8-四氢叶酸（THF，7）与光气、硫光气和溴化氰反应分别生成桥联衍生物5,10-(CO)-THF（8）、5,10-(CS)-THF（9）和5,10-(C = NH)-THF（11）。10-(氯乙酰基)叶酸（2）的催化氢化反应生成5,10-(CH2CO)-THF（12）。10-(3-氯丙酰基)叶酸（3）的类似反应生成10-(ClCH2CH2CO)-THF（14），而非5,10-(CH2CH2CO)-THF（13）。10-乙二酰基叶酸（5）的催化氢化反应中，初始产物10-(EtO2CCO)-THF（22）很容易重排生成5-(EtO2CCO)-THF（21）。THF与氯乙酰氯的酰化反应生成N5,N10-二酰化产物（18或19），该产物无法转化为5,10-(COCH2)-THF（17）。THF分别与乙醛酸和5-羟基戊醛进行还原烷基化反应，生成5-(HO2CCH2)-THF（24）和5-[HO(CH2)5]-THF（25）。THF与甲醛进行还原二烷基化反应生成5,10-(CH3)2-THF（27），而与乙二醛反应生成5,10-(CH2CH2)-THF（10）。此外，叶酸和5-(CHO)-THF均与甲醛进行还原烷基化反应，分别生成10-甲基叶酸（6）和5-(CHO)-10-(CH3)-THF（28）。这些化合物作为叶酸代谢相关酶的抑制剂以及对小鼠淋巴细胞白血病P388的活性进行了测试。
