BIOMAT Database Logo BIOMAT Database Logo

In vitro antitumour activity of cis- and trans-5-fluoro-5,6-dihydro-6-alkoxy-uracils; effects on thymidylate synthesis. 1993

C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Department of Oncology, Free University Hospital, Amsterdam, Netherlands.

A class of new 5-fluorouracil (FU) analogues, the 5-fluoro-5,6-dihydro-6- alkoxy-uracils was synthesised with a modification at the 6-position of the pyrimidine ring. At this position the analogues have a hydroxy or alkoxy group of different chain lengths either in the cis- or trans-configuration. The antiproliferative effect of these compounds was tested on five cell lines of different origin. Generally, the analogues with a cis-configuration had a higher activity than those with a trans-configuration. The growth inhibitory effect of the compounds decreased with increasing alkoxy chain length, but the compound with a hydroxy group had the lowest growth inhibitory effect. One analogue, cis-5-F-5,6-dihydro-6-methoxy-uracil had a higher antiproliferative effect than FU in one of the cell lines. Effects on thymidylate synthase (TS), the possible target of these analogues, were evaluated by thymidine rescue of growth inhibition and incorporation of tritiated deoxyuridine (3H-UdR) into DNA. In solid tumour cell lines addition of TdR reversed the antiproliferative effect. Inhibition of TS in intact cells was determined by measuring 3H-UdR incorporation in two cell lines. The effect of cis-5-F-5,6-dihydro-6-methoxy-uracil on incorporation of 3H-UdR was 2- to 5-fold stronger than that of FU in both cell lines. All other compounds produced a higher 3H-UdR incorporation than FU both at equimolar and equi-toxic concentration. Concluding from these results we regard cis-5-F-5,6-dihydro-6-methoxy-uracil as the most promising FU analogue of this series, because of its higher antiproliferative activity than FU and marked inhibition of TS in intact cells.

UI MeSH Term Description Entries
D007822 Laryngeal Neoplasms Cancers or tumors of the LARYNX or any of its parts: the GLOTTIS; EPIGLOTTIS; LARYNGEAL CARTILAGES; LARYNGEAL MUSCLES; and VOCAL CORDS. Cancer of Larynx,Laryngeal Cancer,Larynx Neoplasms,Cancer of the Larynx,Larynx Cancer,Neoplasms, Laryngeal,Cancer, Laryngeal,Cancer, Larynx,Cancers, Laryngeal,Cancers, Larynx,Laryngeal Cancers,Laryngeal Neoplasm,Larynx Cancers,Larynx Neoplasm,Neoplasm, Laryngeal,Neoplasm, Larynx,Neoplasms, Larynx
D009062 Mouth Neoplasms Tumors or cancer of the MOUTH. Cancer of Mouth,Mouth Cancer,Oral Cancer,Oral Neoplasms,Cancer of the Mouth,Neoplasms, Mouth,Neoplasms, Oral,Cancer, Mouth,Cancer, Oral,Cancers, Mouth,Cancers, Oral,Mouth Cancers,Mouth Neoplasm,Neoplasm, Mouth,Neoplasm, Oral,Oral Cancers,Oral Neoplasm
D002294 Carcinoma, Squamous Cell A carcinoma derived from stratified SQUAMOUS EPITHELIAL CELLS. It may also occur in sites where glandular or columnar epithelium is normally present. (From Stedman, 25th ed) Carcinoma, Epidermoid,Carcinoma, Planocellular,Carcinoma, Squamous,Squamous Cell Carcinoma,Carcinomas, Epidermoid,Carcinomas, Planocellular,Carcinomas, Squamous,Carcinomas, Squamous Cell,Epidermoid Carcinoma,Epidermoid Carcinomas,Planocellular Carcinoma,Planocellular Carcinomas,Squamous Carcinoma,Squamous Carcinomas,Squamous Cell Carcinomas
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D003857 Deoxyuridine 2'-Deoxyuridine. An antimetabolite that is converted to deoxyuridine triphosphate during DNA synthesis. Laboratory suppression of deoxyuridine is used to diagnose megaloblastic anemias due to vitamin B12 and folate deficiencies. (beta 1-(2-Deoxyribopyranosyl))thymidine
D004273 DNA, Neoplasm DNA present in neoplastic tissue. Neoplasm DNA
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D005472 Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid. 5-FU,5-FU Lederle,5-FU Medac,5-Fluorouracil,5-Fluorouracil-Biosyn,5-HU Hexal,5FU,Adrucil,Carac,Efudex,Efudix,Fluoro-Uracile ICN,Fluoroplex,Fluorouracil Mononitrate,Fluorouracil Monopotassium Salt,Fluorouracil Monosodium Salt,Fluorouracil Potassium Salt,Fluorouracil-GRY,Fluorouracile Dakota,Fluorouracilo Ferrer Far,Fluoruracil,Fluracedyl,Flurodex,Haemato-FU,Neofluor,Onkofluor,Ribofluor,5 FU Lederle,5 FU Medac,5 Fluorouracil,5 Fluorouracil Biosyn,5 HU Hexal,Dakota, Fluorouracile,Fluoro Uracile ICN,Fluorouracil GRY,Haemato FU
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013940 Thymidylate Synthase An enzyme of the transferase class that catalyzes the reaction 5,10-methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. Thymidylate Synthetase,Synthase, Thymidylate,Synthetase, Thymidylate

Related Publications

C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils and Their Transformation to 6-Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils, and 4,5,5-Trisubstituted 3-Methyloxazolizin-2-ones.
June 2016, The Journal of organic chemistry,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
[Synthesis of racemic 5,6-cis- and trans-kavain-5-ol].
January 1973, Chemische Berichte,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6-(arylthio)uracils.
July 1997, Journal of medicinal chemistry,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Synthesis and antiviral activity of 5-ethyl-5-halo-6-alkoxy-(or azido)-5,6-dihydro-2'-deoxyuridine diastereomers as potential prodrugs to 5-ethyl-2'-deoxyuridine.
August 1997, Archiv der Pharmazie,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
5-Fluoro- and 5-chlorocyclophosphamide: synthesis, metabolism, and antitumor activity of the cis and trans isomers.
December 1981, Journal of medicinal chemistry,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
5,6-Dihydro-5,6-cyclobutanyluracils and their nucleosides: intermediates in the photochemical dealkylation of 5-propyl- and 5-isopropyl uracils and their nucleosides.
January 1972, Acta biochimica Polonica,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Studies on fluorinated pyrimidines. II. Synthesis and antitumor activity of 5-fluoro-6-substituted-5,6-dihydrouracil-5-carboxylic acid derivatives.
March 1982, Chemical & pharmaceutical bulletin,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Synthesis of substituted 5-fluoro-5,6-dihydropyrimidines.
November 1975, Nucleic acids research,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
6-(2-Fluoro-phen-yl)-5,6-dihydro-benzimidazolo[1,2-c]quinazoline.
October 2008, Acta crystallographica. Section E, Structure reports online,
C L van der Wilt, and G W Visser, and B J Braakhuis, and R Wedzinga, and P Noordhuis, and K Smid, and G J Peters
Synthesis and cytotoxic activity of various 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils in their racemic form.
December 2007, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!