Synthesis and antitumor activity of 5-deaza-5,6,7,8-tetrahydrofolic acid and its N10-substituted analogs

Taylor, Edward C.; Hamby, James M.; Shih, Chuan; Grindey, Gerald B.; Rinzel, Sharon M.; Beardsley, G. Peter; Moran, Richard G.

doi:10.1021/jm00127a019

Cited by 41 publications

(7 citation statements)

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“…10-Methyl-5,8-dideaza-THF, a gift from Dr. M. G. Nair (Nair et al, 1987), whose melting point was determined to be 240 °C (with a published melting point of 235-238 °C), was dissolved in 0.1 N NaOH. 5-Deaza-THF, a gift from Dr. Joe Shih at Lilly Research Laboratories (Taylor et al, 1989), was dissolved in 0.1 N NaOH. The following extinction coefficients were used to quantitate the indicated compounds: 10-methyl-5,8-dideaza-THF, 22 167 M™1 cm-1 at pH 13, X = 312 nm; 5-deaza-THF, 11 900 M™1 cm™1 at pH 13, X = 276 nm (Singh et al, 1991).…”

Section: Methodsmentioning

confidence: 99%

Evidence from 18O Exchange Studies for an Exocyclic Methylene Intermediate in the Reaction Catalyzed by T4 Deoxycytidylate Hydroxymethylase

Butler

Graves²,

Hardy³

1994

Biochemistry

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18O exchange experiments were designed to identify the final intermediate in the catalytic mechanism of bacteriophage T4 deoxycytidylate (dCMP) hydroxymethylase (CH). CH catalyzes the formation of 5-(hydroxymethyl)-dCMP (HmdCMP) from dCMP and methylenetetrahydrofolate (CH2-THF). CH resembles thymidylate synthase (TS), an enzyme of known three-dimensional structure, in both amino acid sequence and the reaction catalyzed. The final intermediate in the reaction catalyzed by TS or CH has been proposed to be the nucleotide with an exocyclic 5-methylene group covalently linked to the enzyme. This intermediate is then hydrated to HmdCMP (by CH) or reduced to deoxythymidylate (by TS). We report here that CH catalyzes the incorporation of 18O from solvent water into the product, HmdCMP, in the presence of tetrahydrofolate (THF). The cause of this exchange is a reverse reaction followed by a resynthesis. CH also catalyzes the exchange of 18O from solvent water into HmdCMP in the absence of exogenous THF and in the presence of THF analogues that lack N-5. N-5 is the nitrogen that is likely to be bound to the methylene as it is transferred to dCMP. A CH variant that lacks the nucleophilic Cys 148 is incapable of promoting these 18O exchange reactions. The THF analogues lacking N-5 do not promote a CH-catalyzed reverse reaction. Rather, we propose that the CH-catalyzed 18O exchange reaction promoted by these THF analogues occurs via 5-methylene-dCMP linked to the enzyme through Cys 148. We conclude here that enzyme-bound 5-methylene-dCMP is the final intermediate during catalysis by CH, as has also been proposed for TS and dUMP.

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Section: Methodsmentioning

confidence: 99%

Evidence from 18O Exchange Studies for an Exocyclic Methylene Intermediate in the Reaction Catalyzed by T4 Deoxycytidylate Hydroxymethylase

Butler

Graves²,

Hardy³

1994

Biochemistry

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“…The failure of the chlorination and thiation of lactam 5 was attributed to the poor solubility of 5. Solubility of some insoluble folic acid analogues were reported 23 to be greatly improved by pivaloylation of the amino groups. The pivaloylated derivative 15 was obtained The product obtained was identical in all respects to 9 described above.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Biological Activities of Conformationally Restricted, Tricyclic Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductases

1997

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Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'-positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCl5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100-fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).

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“…Despite the remarkable biological importance of tetrahydrofolate analogues, not many synthetic approaches have been reported. The common synthesis strategy [12,13,14,15] is based on a critical step which is catalytic hydrogenation of folate derivatives, and was the strategy we used in synthesis of ZL033 and a series of novel 8-deazatetrahydrofolate derivatives as DHFR and MS inhibitors (Scheme 1). The reductive hydrogenation is a critical step in the entire synthetic scheme due to the benzylic hydrogenolysis of the C 9 -N 10 bond as a side reaction.…”

Section: Introductionmentioning

confidence: 99%

Novel Synthesis of 8-Deaza-5,6,7,8-tetrahydroaminopterin Analogues via an Aziridine Intermediate

Zhou

Tian

et al. 2012

Molecules

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An efficient method for the construction of the tetrahydrofolate skeleton is described. Starting from pterin analogues and aromatic amines, 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives and the heterocyclic benzoyl isosteres were synthesized via a novel aziridine intermediate. Following this method, the byproducts of carbonnitrogen bond hydrogenolysis in traditional synthetic strategy can be completely avoided.

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Synthesis and antitumor activity of 5-deaza-5,6,7,8-tetrahydrofolic acid and its N10-substituted analogs

Cited by 41 publications

References 0 publications

Evidence from 18O Exchange Studies for an Exocyclic Methylene Intermediate in the Reaction Catalyzed by T4 Deoxycytidylate Hydroxymethylase

Evidence from 18O Exchange Studies for an Exocyclic Methylene Intermediate in the Reaction Catalyzed by T4 Deoxycytidylate Hydroxymethylase

Synthesis and Biological Activities of Conformationally Restricted, Tricyclic Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductases

Novel Synthesis of 8-Deaza-5,6,7,8-tetrahydroaminopterin Analogues via an Aziridine Intermediate

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