Synthesis of pseudo cofactor analogues as potential inhibitors of the folate enzymes.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005492:Folic Acid / Q000378:metabolism*; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid