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)

• Published in: Journal of medicinal chemistry Vol. 44; no. 14; pp. 2366 - 2369
• Main Authors: Borrell, José I, Teixidó, Jordi, Matallana, Josep Lluís, Martínez-Teipel, Blanca, Colominas, Carles, Costa, Marta, Balcells, Merche, Schuler, Elisabeth, Castillo, María José
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.07.2001; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Escherichia coli - chemistry; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - pharmacology; General aspects; Humans; Hydroxymethyl and Formyl Transferases - chemistry; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphoribosylglycinamide Formyltransferase; Ribonucleotides - chemistry; Science & Technology; Structure-Activity Relationship; Tetrahydrofolates - chemical synthesis; Tetrahydrofolates - chemistry; Tetrahydrofolates - pharmacology; Tumor Cells, Cultured; FOLATE ANTAGONISTS; PURINE SYNTHESIS; PHASE-I; Antineoplastic agent; Human; Nitrogen heterocycle; Lactam; Cytotoxicity; In vitro; Biological activity; α-Aminoacid; Cell line; Bicyclic compound; Dicarboxylic acid; Chemical synthesis; Lymphoblastoid cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990411u

We recently described the syntheses of 12a−c, 4-amino-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), in six steps from commercially available p-substituted methyl benzoates in 20−27% overall yields. Such analogues were tested in vitro against CCRF-CEM leukemia cells and showed that they are completely devoid of any activity, the IC50 being higher than 20 μg/mL for all cases. To clarify if the presence of the carbonyl group in position C7, the distinctive feature of our synthetic methodology, is the reason for this lack of activity, we have now obtained the 7-oxo substituted analogues of 5-DATHF and DDATHF, 18a−c, in 10−30% overall yield. Testing of 18a−c in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active site of the complex E. coli GARTFase-5-DATHF-GAR pointed to an electronic repulsion between the atoms of the 7-oxo group and the carbonyl group of Arg90 as a possible explanation for the inactivity of 18a−c.