Design and synthesis of Cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents(,).
Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.
Bavetsias
V
V
CRC Centre for Cancer Therapeutics at The Institute of Cancer Research, Cancer Research Campaign Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, England.
Marriott
J H
JH
Melin
C
C
Kimbell
R
R
Matusiak
Z S
ZS
Boyle
F T
FT
Jackman
A L
AL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008727:Methotrexate / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014316:Tritium; D014407:Tumor Cells, Cultured
C409862:4-(N-(N-(4-(N-(2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta(g)quinazolin-6-yl)-N-(prop-2-ynyl)amino)benzoyl)-gamma-glutamyl)amino)-4-(5-tetrazolyl)butyric acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D011799:Quinazolines; D014316:Tritium; D013940:Thymidylate Synthase; D008727:Methotrexate