5-Quinone derivatives of 2'-deoxyuridine 5'-phosphate: inhibition and inactivation of thymidylate synthase, antitumor cell, and antiviral studies

• Published in: Journal of medicinal chemistry Vol. 30; no. 2; pp. 409 - 419
• Main Authors: Al-Razzak, Laman A, Schwepler, Douglas, Decedue, Charles J, Balzarini, Jan, De Clercq, Erik, Mertes, Mathias P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.02.1987
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antiviral Agents - chemical synthesis; Carbohydrates. Nucleosides and nucleotides; Cell Division - drug effects; Cell Line; Cell Survival - drug effects; Chemistry; Deoxyuracil Nucleotides - chemical synthesis; Deoxyuracil Nucleotides - pharmacology; Deoxyuracil Nucleotides - toxicity; Exact sciences and technology; Humans; Indicators and Reagents; Kinetics; Lactobacillus casei - enzymology; Leukemia L1210 - enzymology; Mice; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Simplexvirus - drug effects; Structure-Activity Relationship; Thymidylate Synthase - antagonists & inhibitors; Vaccinia virus - drug effects; Vesicular stomatitis Indiana virus - drug effects; Antineoplastic agent; Quinone; Ultraviolet spectrum; Enzyme inhibitor; Antiviral; Deoxyribonucleoside; NMR spectrum; Thymidylate synthase; Pyrimidine nucleoside; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00385a026

Both photochemical aromatic substitution and palladium (0)-catalyzed biaryl coupling reactions have been employed in the synthesis of 5-substituted 2'-deoxyuridines. The former procedure was useful in the preparation of the 3,4-dimethyl-2,5-dimethoxyphenyl derivative 12a and the 3,4,6-trimethyl-2,5-dimethoxyphenyl derivative 12b. The latter reaction was efficient in the preparation of the 2-(3-methyl-1,4-dimethoxynaphthyl) derivative 14. These compounds and their nucleotides (20a-c) were converted to the corresponding quinone nucleosides 19a-c and nucleotides 6-8 by an oxidative demethylation reaction using ceric ammonium nitrate and silver(II) oxide, respectively. The kinetics and products of the reaction of the quinone nucleosides 19a,b with methyl thioglycolate showed rapid addition to the quinone ring in the trisubstituted derivative 19a and somewhat slower redox reactions with the tetrasubstituted quinones 19b and 19c. All six nucleotides had high affinity for the title enzyme from Lactobacillus casei with Ki values ranging from 0.59 to 3.6 microM; the most effective compounds were the dimethyl quinone 6 and the naphthoquinone 8. Somewhat higher inhibitory constants were observed with the quinones against the L1210 enzyme. The dimethyl quinone nucleotide 6 showed time-dependent inactivation (kinact = 0.015 s-1) against the L. casei enzyme, a rate saturation effect, and substrate protection in accord with the kinetic expression for an active-site-directed alkylating agent. The apparent second-order rate of this reaction (2.5 X 10(4) M-1 s-1) is one-twentieth the rate (kcat.) of the normal enzymatic reaction leading to product. None of the compound exhibited sufficient activity in the antitumor cell or antiviral assays to warrant further study.