Dialkyl esters of methotrexate and 3',5'-dichloromethotrexate: synthesis and interaction with aldehyde oxidase and dihydrofolate reductase.

摘要: A series of lipid-soluble dialkyl esters methotrexate and 39,59-dichloromethotrexate have been prepared their properties as substrates for rabbit liver aldehyde oxidase and inhibitors mouse leukemia L1210 dihydrofolate reductase examined. The short-chain esters are highly active oxidase, being converted to the corresponding 7-hydroxy derivatives; Michaelis constants hydroxylation reaction are in range of 0.002-0.005 mM, 10- 100-fold lower than previously described this enzyme. Increases ester chain length accompanied by increased lipid solubility and decreased substrate activity. With nonesterified parent compound, methotrexate, the Michaelis constant decreases oxidation rate increases with decreasing pH throughout the physiological range; esters, on other hand, a well-defined maximum in apparent affinity is seen at 8. This disparity behavior two types supports hypothesis that activity nonesterified parent compound property undissociated carboxylic acid, rather anionic form, apparent enhancement due to their inability form latter. As inhibitors reductase, are 2- 10-fold less effective methotrexate; inhibitory increasing chain length. inhibition observed di-n-amyl di-n-octyl esters methotrexate.