title: Folate analogues. 31. Synthesis of the reduced derivatives of 11-deazahomofolic acid, 10-methyl-11-deazahomofolic acid, and their evaluation as inhibitors of glycinamide ribonucleotide formyltransferase.
abstract: The Boon-Leigh procedure, involving condensation of a 6-chloro-5-nitropyrimidine (22) with an alpha-amino ketone (20 or 21) followed by reduction of the nitro group, cyclization, and L-glutamylation, led to the formation of 11-deazahomofolate (29) and its 10-methyl derivative (30). The corresponding (6R,S)-5,6,7,8-tetrahydro (4, 5) and 7,8-dihydro (31, 32) derivatives were prepared by catalytic hydrogenation. (6S)-11-Deazatetrahydrohomofolate was prepared from 29 by enzymatic reduction. Compounds 29 and 30 had little effect (IC50 greater than 2 x 10(-5) M) on Lactobacillus casei glycinamide ribonucleotide (GAR) formyltransferase but (6R,S)-11-deazatetrahydrohomofolate (4) is a potent inhibitor of this enzyme (IC50 = 5 x 10(-8) M). It is at least 100 times more inhibitory than 33, the 6S compound, indicating that the 6R component of the mixture having the unnatural configuration at C6 (34) is responsible for the potent inhibition. Compound 4 is a much weaker inhibitor of murine (L1210) and human (MOLT-4) leukemia cell GAR formyltransferases (IC50 greater than 1 x 10(-5) M). (6R,S)-11-Deaza-10-methyltetrahydrohomofolate (5) (IC50 = 1.1 x 10(-5) is 200 times weaker than 4 against L. casei GAR formyltransferase. However, 11-deaza-10-methyldihydrohomofolate (32) is more inhibitory (IC50 = 5.5 x 10(-7) M) than 5 or 30. None of the compounds showed inhibition of L. casei aminoimidazolecarboxamide ribonucleotide (AICAR) formyltransferase, dihydrofolate reductase, or thymidylate synthase. The dihydro derivatives 31 and 32 are 5% as active as dihydrofolate as substrates for L. casei dihydrofolate reductase. Compound 4 showed moderate inhibition of the growth of L. casei, Streptococcus faecium, MOLT-4 cells, and MCF-7 human breast adenocarcinoma cells.
authors.affiliation: Department of Biochemistry, University of South Alabama, Mobile 36688.
authors.forename: M G
authors.initials: MG
authors.lastname: Nair
authors.forename: B R
authors.initials: BR
authors.lastname: Murthy
authors.forename: S D
authors.initials: SD
authors.lastname: Patil
authors.forename: R L
authors.initials: RL
authors.lastname: Kisliuk
authors.forename: J
authors.initials: J
authors.lastname: Thorndike
authors.forename: Y
authors.initials: Y
authors.lastname: Gaumont
authors.forename: R
authors.initials: R
authors.lastname: Ferone
authors.forename: D S
authors.initials: DS
authors.lastname: Duch
authors.forename: M P
authors.initials: MP
authors.lastname: Edelstein
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000201:enzymology; D007938:Leukemia / Q000188:drug therapy; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D051026:Phosphoribosylglycinamide Formyltransferase; D011687:Purines / Q000096:biosynthesis*; D013237:Stereoisomerism; D013291:Streptococcus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; C059965:11-deazahomofolic acid; C059964:10-methyl-11-deazahomofolic acid; D005492:Folic Acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases