TY - JOUR
T1 - Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-γ,γ-difluoromethotrexate
AU - Tsukamoto, Takashi
AU - Kitazume, Tomoya
AU - McGuire, John J.
AU - Coward, James K.
PY - 1996/1/5
Y1 - 1996/1/5
N2 - DL-4,4-Difluoroglutamic acid (DL-4,4-F2Glu) and its methotrexate analogue, DL-γ,γ-difluoromethotrexate (DL-γ,γ-F2MTX), were synthesized and evaluated as alternate substrates or inhibitors of folate-dependent enzymes. Synthesis of DL-4,4-F2Glu involved the nitroaldol reaction of ethyl nitroacetate with a difluorinated aldehyde ethyl hemiacetal as a key step. Attempted ligation of DL-4,4-F2Glu to methotrexate (MTX), catalyzed by human folylpoly-γ-glutamate synthetase (FPGS), revealed that DL-4,4-F2Glu is a poor alternate substrate. DL-γ,γ-F2MTX was synthesized by a route proceeding through N-[4-(methylamino)benzoyl]-4,4-difluoroglutamic acid di- tert-butyl ester followed by alkylation with 6-(bromomethy])-2,4- pteridinediamine hydrobromide. DL-γ,γ-F2MTX was found to be neither a substrate nor an inhibitor of human FPGS. The fluorinated analogue of MTX, however, inhibits DHFR and cell growth with the same potency as MTX.
AB - DL-4,4-Difluoroglutamic acid (DL-4,4-F2Glu) and its methotrexate analogue, DL-γ,γ-difluoromethotrexate (DL-γ,γ-F2MTX), were synthesized and evaluated as alternate substrates or inhibitors of folate-dependent enzymes. Synthesis of DL-4,4-F2Glu involved the nitroaldol reaction of ethyl nitroacetate with a difluorinated aldehyde ethyl hemiacetal as a key step. Attempted ligation of DL-4,4-F2Glu to methotrexate (MTX), catalyzed by human folylpoly-γ-glutamate synthetase (FPGS), revealed that DL-4,4-F2Glu is a poor alternate substrate. DL-γ,γ-F2MTX was synthesized by a route proceeding through N-[4-(methylamino)benzoyl]-4,4-difluoroglutamic acid di- tert-butyl ester followed by alkylation with 6-(bromomethy])-2,4- pteridinediamine hydrobromide. DL-γ,γ-F2MTX was found to be neither a substrate nor an inhibitor of human FPGS. The fluorinated analogue of MTX, however, inhibits DHFR and cell growth with the same potency as MTX.
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U2 - 10.1021/jm950514m
DO - 10.1021/jm950514m
M3 - Article
C2 - 8568828
AN - SCOPUS:0030052336
SN - 0022-2623
VL - 39
SP - 66
EP - 72
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -