Enantiospecific syntheses of alpha-(fluoromethyl)tryptophan analogues: interactions with tryptophan hydroxylase and aromatic L-amino acid decarboxylase.
alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Our goal is to utilize antagonists of the serotonin-producing enzymes (tryptophan hydroxylase and AADC) as the basis for a chemotherapeutic approach to the treatment of carcinoid tumors, a rare tumor type characterized by the overproduction of serotonin. We report here an enantiospecific synthesis of alpha(S)-(fluoromethyl)tryptophan [(S)-11a] and alpha(S)-(fluoromethyl)-5-hydroxytryptophan [(S)-11b], as well as the (R)-enantiomers, based upon recent methodology involving the face-selective alkylation of cyclic tryptophan tautomers. Our synthetic route provided both enantiomers of 11a and 11b with greater than 97% enantiomeric purity based upon evaluation of the NMR spectra of their Mosher's acid derivatives. (S)-11a was evaluated as a substrate for P815 tryptophan hydroxylase and determined to have an apparent Km of 4.31 +/- 1.07 mM, essentially half the value previously reported for the racemic mixture of 11a with rat brain stem tryptophan hydroxylase. (R)-11a was not a substrate for P815 tryptophan hydroxylase. (S)-11b was evaluated as an enzyme-activated irreversible inhibitor of murine liver AADC and determined to have a KI of 24.3 +/- 3.01 microM and a k2 of 2.26 +/- 0.44 min-1. (R)-11b was not an inhibitor of murine liver AADC.
Zembower
D E
DE
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Gilbert
J A
JA
Ames
M M
MM
D006916:5-Hydroxytryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D051379:Mice; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000201:enzymology
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; C079444:alpha-(fluoromethyl)-5-hydroxytryptophan; C079443:alpha-(fluoromethyl)tryptophan; D014364:Tryptophan; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase