Folic acid derivatives

Table 3. Physical Properties of Folic Acid Derivatives...

Folic acid derivatives (folates) are acceptors and donors of one-carbon units for all oxidation levels of carbon except that of CO2 (where biotin is the relevant carrier). The active coenzyme form of folic acid is tetrahydrofolate (THF). THF is formed via two successive reductions of folate by dihydrofolate reductase (Figure 18.35). One-carbon units in three different oxidation states may be bound to tetrahydrofolate at the and/or nitrogens (Table 18.6). These one-carbon units... 

Lee, J. (1990). Lumazine protein and the bioluminescence of Photobacterium. In Curtius, H.-C., et al. (eds.), Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 9th, 1989, pp. 445-456. de Gruyter, Berlin. 

Folic acid derivatives are important in the production of purines and deoxythy-midine monophosphate (dTMP, a pyrimidine) required for nucleic acid synthesis in... 

Recently, Choy et al. also reported that LDHs are an efficient drug reservoir for folate derivatives [187]. Folic acid derivatives, folinic acid and methotrexate (MTX), have been successfully hybridized with Mg/Al LDHs by ion-exchange reactions. Cellular uptake tests with the MTX-LDH hybrids were carried out in the fibroblast (human tendon) and osteosarcoma (SaOS-2) cell lines by in vitro assay. They found that the LDH not only plays a role as a biocompatible delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency. 

Folic acid is a vitamin, as we developed in chapter 15. It is a complex molecule that serves as an essential precursor for coenzymes involved in the metabolism of one-carbon units. For example, folic acid-derived coenzymes are critically involved in the biosynthesis of thymidine for nucleic acid synthesis and methionine for protein biosynthesis. The synthesis of both demands donation of a methyl group and they come from folic acid-derived coenzymes. 

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

Folic acid derivatives are essential for DNA synthesis, in that they are cofactors for certain reactions in purine and pyrimidine biosynthesis, including the uracil-thymine methylation just described. They are also cofactors for several reactions relating to amino acid metabolism. The folic acid system thus offers considerable scope for drug action. 

Other NADH dehydrogenases include NADH dehydrogenase (quinone) [EC 1.6.99.5] which catalyzes the reaction of NADH with an acceptor to produce NAD+ and the reduced acceptor. Menaquinone can serve as the acceptor substrate. This dehydrogenase is inhibited by AMP and 2,4-dinitrophenol but not by dicoumarol or folic acid derivatives. 

Folic acid derivatives folate, 7,8-dihydrofolate, Bu N--l>0< Me0H-H,0 (35 65) Ocnidccyl 238... 

Leucovorin (Wellcovorin) [Folic Acid Derivative/Vitamin]... 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

The life cycle of Dictyostelium discoideum is described briefly in Box 11-C. About 105 individual amebas aggregate to form a moving "slug" in response to the chemoattractant cAMP. Some other species of Dictyostelium are attracted to a folic acid derivative or to the ethyl ester of N-propionyl-y-L-glutamyl-L-omithine-5-lactam 226... 

Coward, J. K. McGuire, J.J. Galivan, J. in Chemistry and Biology of Pteridines 1989. Pteridines and Folic Acid Derivatives. Proceedings of the Ninth International Symposium on Pteridines and Folic Acid Derivatives. Chemical, Biological and Clinical Aspects, Zurich, Switzerland, Sept 3-8, 1989 Curtius, H.-C. Ghisla, S. Blau, N Eds. dc Gruyter Berlin, 1990 pp 1198 1202. 

G. C.K. Roberts, in Chemistry and Biology of Pteridines Pteridines and Folic Acid Derivatives, ed. J.A. Blair (Walter de Gruyter, Berlin, 1983) p. 197. 

J.R. Piper, G.S. McCaleb, J.A. Montgomery and F.M. Sirotnak, 8th International Symposium on Pteridines and Folic Acid Derivatives Chemical, Biological and Clinical Aspects (June 15-20, 1986), Montreal, Canada. We thank Dr. J.R. Piper for providing us with a preprint of this work prior to publication. 

Figure 13.18 A ribbon structure of a folic acid derivative self-assembles into a disc-like tetramer based on a G-quartet motif showing liquid crystalline behaviour on the addition of a metal ion such as Na+.

A metabolic pathway that has received considerable attention is the conversion of 2 -deoxyuridine 5 -monophosphate (dUMP, 6.60) to thymidine 5 -monophosphate (TMP, 6.61) (Scheme 6.13). Without an adequate supply of TMP, a cell or bacterium cannot create DNA for cell division. Therefore, blocking TMP synthesis is an attractive method for slowing the advancement of certain cancers and bacterial infections. Important molecules in the methylation of dUMP are the various folic acid derivatives folic acid (FA, 6.62), dihydrofolic acid (DHF, 6.63), tetrahydrofolic acid (THF, 6.64), and N5, A1 "-methylene tetrahydrofolic acid (MTHF, 6.65) (Figure 6.23). These structures... 

The preparation of a cubic phase with supramolecular chirality was achieved using a branched folic acid derivative incorporating glutamic acid residues (Fig. 11) as the source of chirality [93]. The pterin rings of folic acid residues are able to form a cyclic tetramer as a result of two hydrogen bonds between the components. Depending on the number of carbon atoms in the alkyl substituents, the compounds form columnar phases over a wide temperature range, and for 8 and 9 form cubic phases at temperatures above 130 °C. Addition of sodium triflate stabilises the cubic phase for 7, and the salt is incorporated into the other mesophases. It was implied that the cation resides between stacked tetramers. Supramolecular chirality is expressed for both the columnar and the cubic phases, as revealed by vari-... 

Fig. 11 The chiral folic acid derivatives 7, 8 and 9, which display mesophases thanks to the formation of a supramolecular cyclic tetramer by the pterin rings (right) [93]...

II.1 Folic Acid Derivatives 7.18.11.2 Folic Acid Analogues... 

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