Analogs of methotrexate

Piper, James R.; Elliott, Robert D.; Temple, Carroll; Roberts, Edward; Shealy, Y. Fulmer

doi:10.1021/jm00193a021

Cited by 41 publications

(14 citation statements)

References 9 publications

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“…Lastly, PMB deprotection under acidic conditions afforded the prodrug 17. 57 for similar substrates. The last step consisted of alkaline hydrolysis of 24 to form the second AMT prodrug 25.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Cadahía

Bondebjerg

Hansen³

et al. 2018

J. Med. Chem.

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A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of HO proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Cadahía

Bondebjerg

Hansen³

et al. 2018

J. Med. Chem.

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“…1), including ICI 198583, N 10 -propargyl-5,8-dideazafolate (CB 3717), N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl ference of the applied substitution with cellular uptake and/or polyglutamylation. It should be mentioned that phenylacetyl analogues of folate (Roberts & Shealy, 1973) and aminopterin (Montgomery et al, 1979) have been synthesized and tested against dihydrofolate reductase and cell growth. A CH 2 spacer inserted between the phenyl and CONH moiety caused a marked decrease in affinity of the enzyme for the new analogues, as compared with the parent compounds, but was much more detrimental to the potential of either phenylacetyl analogue to influence cell growth.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological activity of N(alpha)-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenylacetyl]-L-glutamic acid.

Kusakiewicz-Dawid

Bugaj²,

Dzik³

et al. 2002

Acta Biochim Pol

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2-Deamino-2-methyl-N 10 -propargyl-5,8-dideazafolic acid (ICI 198583) is a potent inhibitor of thymidylate synthase. Its analogue, N a -[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenylacetyl]-L-glutamic acid, containing p-aminophenylacetic acid residue substituting p-aminobenzoic acid residue, was synthesized. The new analogue exhibited a moderately potent thymidylate synthase inhibition, of linear mixed type vs. the cofactor, N 5,10 -methylenetetrahydrofolate. The K i value of 0.34 mM, determined with a purified recombinant rat hepatoma enzyme, was about 30-fold higher than that reported for inhibition of thymidylate synthase from mouse leukemia L1210 cells by ICI 198583 ( Hughes et al., 1990, J. Med. Chem. 33, 3060). Growth of mouse leukemia L5178Y cells was inhibited by the analogue (IC 50 = 1.26 mM) 180-fold weaker than by ICI 198583 (IC 50 = 6.9 mM).

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“…A specific charge interaction between the acarboxylate of the L-glutamate moiety of MTX and an invariant arginine residue has been implicated in the binding of MTX to DHFR. The importance of a free a-carboxylate on the MTX molecule for binding has been further substantiated from the studies with a-and ycarboxyl-modified MTX derivatives (Montgomery et al, 1979;Piper et al, 1982;Rosowsky et al, 1981a,b). These studies indicate that the presence of various groups on the y-carboxylate of MTX does not significantly alter the binding of these MTX derivatives to DHFR as evidenced from the inhibition studies.…”

Section: Synthesis Of Lysine and Ornithine Analogues Of Mtxmentioning

confidence: 98%

Analogues of folate antagonists as affinity and fluorescent probes of dihydrofolate reductase structure and function

Freisheim

Price

Kumar

et al. 1986

Biochemical Society Transactions

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Dihydrofolate reductase (DHFR; tetrahydrofolate; NADP' oxidoreductase, EC 1.5.1.3) catalyses the NADPH-dependent reduction of 7,8-dihydrofolate (FAH,) to 5,6,7,8-tetrahydrofolate (FAH,). The coenzyme FAH, serves as a carrier of one-carbon fragments in a number of biosynthetic transfer reactions (Rader & Huennekens, 1973). It is apparent that DHFR is the intracellular target for the anti-cancer drug methotrexate (MTX) as well as the anti-bacterial drug trimethoprim. As a target site for chemotherapeutic agents, DHFR is intimately involved in the continuous synthesis of thymidylate (dTMP). Thymidylate synthase (EC 2.1.1.45) catalyses the reductive methylation of 2'-deoxyuridylate (dUMP) to dTMP in the presence of N5,N"-methylene FAH,. The latter compound not only supplies the onecarbon unit to the 5'-position of the uracil ring of dUMP, but also serves as a reductant supplying a hydrogen from C-6 of the reduced pyrazine ring of FAH,, yielding FAH,. Thus, FAH, must be regenerated via the DHFRcatalysed reaction in order to maintain the intracellular pool of FAH, one-carbon derivatives for both dTMP and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists such as MTX results in a deficiency in the cellular pools of dTMP and purines and thus in a decrease in nucleic acid synthesis. It is the latter property of folate antagonists that has found clinical applications in the treatment of a number of neoplastic disorders and microbial infections. Structural studies of this enzyme from both bacterial and animal sources have been aided by the fact that the M, of many prokaryotic and eukaryotic DHFRs is in the range 1800CL22000.

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Analogs of methotrexate

Cited by 41 publications

References 9 publications

Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

Synthesis and biological activity of N(alpha)-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-propargylamino]phenylacetyl]-L-glutamic acid.

Analogues of folate antagonists as affinity and fluorescent probes of dihydrofolate reductase structure and function

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