BIOMAT Database Logo BIOMAT Database Logo

Synthesis and biological evaluation of 5-deazaisofolic acid, 5-deaza-5,6,7,8-tetrahydroisofolic acid, and their N9-substituted analogues. 1991

S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston 29425.

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.

UI MeSH Term Description Entries
D005492 Folic Acid A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (POACEAE). Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. Pteroylglutamic Acid,Vitamin M,Folacin,Folate,Folic Acid, (D)-Isomer,Folic Acid, (DL)-Isomer,Folic Acid, Calcium Salt (1:1),Folic Acid, Monopotassium Salt,Folic Acid, Monosodium Salt,Folic Acid, Potassium Salt,Folic Acid, Sodium Salt,Folvite,Vitamin B9,B9, Vitamin
D005493 Folic Acid Antagonists Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) Antifolate,Antifolates,Dihydrofolate Reductase Inhibitor,Folic Acid Antagonist,Dihydrofolate Reductase Inhibitors,Folic Acid Metabolism Inhibitors,Acid Antagonist, Folic,Acid Antagonists, Folic,Antagonist, Folic Acid,Antagonists, Folic Acid,Inhibitor, Dihydrofolate Reductase,Inhibitors, Dihydrofolate Reductase,Reductase Inhibitor, Dihydrofolate,Reductase Inhibitors, Dihydrofolate
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013552 Swine Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA). Phacochoerus,Pigs,Suidae,Warthogs,Wart Hogs,Hog, Wart,Hogs, Wart,Wart Hog
D013763 Tetrahydrofolates Compounds based on 5,6,7,8-tetrahydrofolate.
D013940 Thymidylate Synthase An enzyme of the transferase class that catalyzes the reaction 5,10-methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. Thymidylate Synthetase,Synthase, Thymidylate,Synthetase, Thymidylate

Related Publications

S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological activity of 7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF).
July 2001, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and antitumor activity of 5-deaza-5,6,7,8-tetrahydrofolic acid and its N10-substituted analogues.
July 1989, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological activity of 4-amino-7-oxo-substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid and 5,10-dideaza-5, 6,7,8-tetrahydrofolic acid.
August 1998, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological evaluation of N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine.
May 1992, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological activities of 5-deaza analogues of aminopterin and folic acid.
May 1986, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Folate analogues. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogues of N10-propargyl-5,8-dideazafolic acid.
September 1991, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Novel synthesis of 8-deaza-5,6,7,8-tetrahydroaminopterin analogues via an aziridine intermediate.
May 2012, Molecules (Basel, Switzerland),
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.
November 2017, European journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis and biological activity of acyclic analogues of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid.
March 1992, Journal of medicinal chemistry,
S K Singh, and I K Dev, and D S Duch, and R Ferone, and G K Smith, and J H Freisheim, and J B Hynes
Synthesis of 5-substituted 2'-deoxyuridine-5'- phosphonate analogues and evaluation of their antiviral activity.
January 2012, Nucleosides, nucleotides & nucleic acids,
Copied contents to your clipboard!