Syntheses and thymidylate synthase inhibitory activity of the poly-.gamma.-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates

Bisset, G. M. F.; Pawelczak, Krzysztof; Jackman, A L; Calvert, A. H.; Hughes, Laura E.

doi:10.1021/jm00083a008

Cited by 38 publications

(16 citation statements)

References 3 publications

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“…Further, polyglutamylation provides for a significant increase in inhibitory activity against TS compared to the monoglutamates. 34,35,[37][38][39][40] It has been shown for both ZD1694 34 and LY231514 35 that the conversion of the monoglutamate form of these compounds to their pentaglutamates produces a 60-fold (for ZD1694) to 130-fold (for LY231514) increase in TS inhibition. Though polyglutamylation for many antifolates is necessary for cytotoxicity to tumor cells, it has also been implicated in adverse effects on normal tissues due to retention of poly-γ-glutamate metabolites.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent

Gangjee

McGuire

et al. 2000

J. Med. Chem.

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A novel N-¿2-amino-4-methyl[(pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl¿-L-glutamic acid (3a) was designed and synthesized as a potent dual inhibitor of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as an antitumor agent. Compound 3b, the N7-benzylated analogue of 3a, was also synthesized as an antitumor agent. The synthesis of 3a was accomplished via a 12-step sequence which involved the synthesis of 2-amino-4-methylpyrrolo[2,3-d]pyrimidine (10) in 5 steps from 2-acetylbutyrolactone. Protection of the 2-amino group of 10 and regioselective iodination at the 5-position followed by palladium-catalyzed coupling afforded intermediate 14 which was converted to 3a by reduction and saponification. Similar synthetic methodology was used for 3b. X-ray crystal structure of the ternary complex of 3a, DHFR, and NADPH showed that the pyrrolo[2, 3-d]pyrimidine ring binds in a "2,4-diamino mode" in which the pyrrole nitrogen mimics the 4-amino moiety of 2,4-diaminopyrimidines. This is the first example of a classical pyrrolo[2,3-d]pyrimidine antifolate shown to have this alternate mode of binding to DHFR. Compounds 3a and 3b were more inhibitory than LY231514 against TS from Lactobacillus casei and Escherichia coli. Analogue 3a was also more inhibitory against DHFR from human, Toxoplasma gondii, and Pneumocystis carinii. Evaluation of 3a against methotrexate (MTX)-resistant cell lines with defined mechanisms indicated that cross-resistance of 3a was much lower than that of MTX. Metabolite protection studies and folylpoly-gamma-glutamate synthetase studies suggest that the antitumor activity of 3a against the growth of tumor cells in culture is a result of dual inhibition of TS and DHFR. Compound 3a inhibited the growth of CCRF-CEM and FaDu cells in culture at ED(50) values of 12.5 and 7.0 nM, respectively, and was more active against FaDu cells than MTX. In contrast, compound 3b was inactive against both cell lines. Compound 3a was evaluated in the National Cancer Institute in vitro preclinical antitumor screening program and afforded IG(50) values in the nanomolar range against a number of tumor cell lines.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent

Gangjee

McGuire

et al. 2000

J. Med. Chem.

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“…26 In addition, several synthetic strategies have been developed for the synthesis of poly-y-glutamyl forms of folates and antifolates employing either conventional solution or solid peptide chemistry. 23 Our approach to the synthesis of y-linked dipeptides and amide analogues of ICI 198583 is summarized in Scheme 1. It involves the strategy applied for the synthesis of pteroyloligo-y-glutamates36 and the polyy-glutamates of ICI 198583.23 Z-blocked dipeptides 7-16, 18, and 19 were prepared by condensing a-tertbutyl-TV-(benzyloxycarbonyl)-L-glutamic acid (5)37 with the appropriate L-amino acid 6 using the mixed carbonic anhydride method.…”

Section: Introductionmentioning

confidence: 99%

The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Bavetsias²,

Tj³

et al. 1994

J. Med. Chem.

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Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.

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“…6 (7) This was prepared from the above benzyloxycarbonyl compound by hydrogenolysis according to ref. 6 and immediately used in the beneath coupling reaction.…”

Section: Hepta-t-butyl N-[n-[n-[n-[n-[n-(benzyloxycarbonyl)-l-y-glutamentioning

confidence: 99%

“…The synthesis of any antifolate y-oligo(L-glutamyl) conjugate is rather labourious and is therefore performed, as a rule, in solid phase, but unequivocally characterized products were obtained by conven tional solution peptide chemistry (5)(6)(7)(8). Herein we report on a simple synthesis in solution, of the series of six consecutive t-butyl N-(4-propargylaminobenzoyl)-y-oligo(L-glutamate)s (8-13) containing from two to seven L-glutamic acid residues (Scheme 1).…”

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confidence: 99%

An Improved Synthesis of t-Butyl N-(4-propargylaminobenzoyl)-γ-oligo (L-glutamate )s

1995

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SummaryA simple synthesis in solution, of the series of six consecutive t-butyl N-(4-propargylaminobenzoyl)-yoligo(L-glutamate)s (8-13) containing from two to seven L-glutamic acid residues (Scheme 1) is described. a-t-Butyl N-(4-propargylaminobenzoyl)-L-glutamate (1), the versatile synthon is coupled with one of the t-butyl y-oligo(L-glutamate)s (2-7) by means of 2-chloro-l-methylpyridinium tosylate to give the title compounds in 91-95% yield subsequent to edulcoration of a post-reaction mixture and crystallization. These compounds were characterized by melting points, elemental analyses and HPLC and are 96.7-100.0% pure according to the last method (Table I).

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Syntheses and thymidylate synthase inhibitory activity of the poly-.gamma.-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates

Cited by 38 publications

References 3 publications

Design, Synthesis, and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent

Design, Synthesis, and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent

The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

An Improved Synthesis of t-Butyl N-(4-propargylaminobenzoyl)-γ-oligo (L-glutamate )s

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