Quinazoline antifolates thymidylate synthase inhibitors: Lipophilic analogues with modification to the C2-methyl substituent

Journal of Medicinal Chemistry

Volumn 39, Issue 3, 1996, Pages 695-704

  Hennequin, Laurent F ^a   Boyle, F Thomas ^b   Wardleworth, J Michael ^b   Marsham, Peter R ^b   Kimbell, Rosemary ^c   Jackman, Ann L ^c  

^a Centre de Recherches   (France)

^b ASTRAZENECA   (United Kingdom)

^c INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; 2 DEAMINO 2 METHYL 10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; 4 [N [(3,4 DIHYDRO 2 METHYL 4 OXO 6 QUINAZOLINYL)METHYL] N (2 PROPYNYL)AMINO] N (3 NITROBENZYL)BENZAMIDE; FOLATE BINDING PROTEIN; PIPERAZINE DERIVATIVE; QUINAZOLINE DERIVATIVE; RALTITREXED; THYMIDYLATE SYNTHASE; UNCLASSIFIED DRUG;

ARTICLE; BREAST CANCER; CELL GROWTH; CELL MEMBRANE POTENTIAL; DIFFUSION; DRUG RESISTANCE; ENZYME INHIBITION; ENZYME INHIBITOR COMPLEX; LIPOPHILICITY; NEPHROTOXICITY; OVARY CANCER;

ANIMALS; FOLIC ACID ANTAGONISTS; LEUKEMIA L1210; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MICE; QUINAZOLINES; THYMIDYLATE SYNTHASE; TUMOR CELLS, CULTURED; X-RAY DIFFRACTION;

EID: 0030022877     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950645n     Document Type: Article

References (44)

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26. Numbering shown on generic formula of Table 1.
27. 4 buffer at pH 7.0 and 25°C: 2, Sol = 3.2 mg/mL; 41, Sol > 5 mg/mL. Also a 10-fold improvement of the solubility has been observed in favor of the C2-hydroxymethyl derivative compared to that of the C2-methyl counterpart in a series of closely related glutamate-modified TS inhibitors (unpublished data).
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31. Synonyms: NSC 339638, 5,6-dihydro-6-(3,6,13-trihydroxy-3-methyl-4-phosphonoxy-1,7,9,11- tridecatetraenyl)-2H-pyran-2-one monosodium salt.
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38. The E. coli-TS enzyme C-terminal residues Val-Ala-Ile are replaced by Met-Ala-Val in the human enzyme.
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41. 2) = 6.95.
42. a (MeN) = 9.8.
43. 2O) C, H, N.
44. The solubilities have been measured by Dr. D. Leahy's group of Zeneca Pharmaceuticals.