139988-46-8Relevant articles and documents
Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues
Rosowsky, Andre,Forsch, Ronald A.,Wright, Joel E.
, p. 6958 - 6963 (2004)
Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH2 bridge were synthesized and tested for in vitro antifolate activity. The Ki of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was 10-methyl substitution is amplified in the bridged compounds. The Ki values of 9 and 10 as inhibitors of [3H]MTX influx into CCRF-CEM human leukemia cells via the reduced folate carrier (RFC) were 0.28 and 1.1 μM, respectively. The corresponding Ki and Kt values determined earlier for AMT and MTX were 5.4 and 4.7 μM, respectively. Thus, in contrast to its unfavorable effect on DHFR binding, the CH2 bridge increased RFC binding. In a 72 h growth assay with CCRF-CEM cells, the IC50 valuess of 9 and 10 were 5.1 and 140 nM, respectively, a 27-fold difference that was qualitatively consistent with the observed combination of weaker DHFR binding and stronger RFC binding. Although rotationally restricted inhibitors of other enzymes of folate pathway enzymes have been described previously, 9 and 10 are the first reported examples of DHFR inhibitors of this type.
