Synthesis and biological evaluation of 5-deazaisofolic acid, 5-deaza-5,6,7,8-tetrahydroisofolic acid, and their N9-substituted analogues.
Prompted by recent disclosures concerning the potent antitumor activities of 5-deaza-5,6,7,8-tetrahydrofolic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), we have prepared 5-deazaisofolic acid (3a) and 5-deaza-5,6,7,8-tetrahydroisofolic acid (4a). Reductive condensation of 2,6-diamino-3,4-dihydro-4- oxopyrido[2,3-d]pyrimidine with di-tert-butyl N-(4-formylbenzoyl)-L-glutamate and subsequent deprotection with trifluoroacetic acid yielded 5-deazaisofolic acid in good yield. Catalytic hydrogenation of this analogue then gave 4a. The 9-CH3 and 9-CHO modifications of 3a and the 9-CH3 derivative of 4a were also synthesized. Each of the new analogues was evaluated with a variety of folate-requiring enzymes as well as MCF-7 cells in culture. Compound 4a had an IC50 of ca. 1 microM against MCF-7 cells and was nearly 100-fold less potent than DDATHF in this regard. The three oxidized isofolate analogues were all poor inhibitors of tumor cell growth.
Singh
S K
SK
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.
Dev
I K
IK
Duch
D S
DS
Ferone
R
R
Smith
G K
GK
Freisheim
J H
JH
Hynes
J B
JB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D005493:Folic Acid Antagonists; D006801:Humans; D013329:Structure-Activity Relationship; D013552:Swine; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C060147:5-deaza-5,6,7,8-tetrahydrofolic acid; C067391:5-deazaisofolic acid; C067392:5-deaza-5,6,7,8-tetrahydroisofolic acid; C045894:lometrexol; D005492:Folic Acid; D013940:Thymidylate Synthase