Quinoline antifolate thymidylate synthase inhibitors: variation of the C2- and C4-substituents.
Modifications to the bicyclic ring system of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (1, CB3717) have led to the synthesis of a series of quinoline antifolates bearing a variety of substituents at the C2 and C4 positions. In general the synthetic route involved the coupling of the appropriate diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate with a disubstituted 6-(bromomethyl)quinoline followed by deprotection using mild alkali. The compounds were tested as inhibitors of partially purified L1210 TS. As a measure of cytotoxicity, the compounds were tested for their inhibition of the growth of L1210 cells in culture. Good enzyme inhibition and cytotoxicity were found for compounds containing chloro, amino, or methyl substituents at the C2 position with chloro or bromo substituents at C4. The effect on enzyme inhibition of varying the N10 substituent of 2h was similar to that observed in the quinazolinone-containing antifolates, indicating that the quinoline compounds may be interacting with the enzyme in a similar way to the quinazolinones. Also, the introduction of a 2'-fluoro substituent into the benzoyl ring of several of the quinoline antifolates led to an increase in both TS inhibition and the inhibition of L1210 cell growth. These data demonstrate that the N3-H of the pyrimidine ring of the quinazolinone antifolates is not required for binding to TS if appropriate substituents are placed at the C2 and C4 positions of the bicyclic ring system.
Warner
P
P
Department of Chemistry, ICI Pharmaceuticals, Macclefield, Cheshire, UK.
Barker
A J
AJ
Jackman
A L
AL
Burrows
K D
KD
Roberts
N
N
Bishop
J A
JA
O'Connor
B M
BM
Hughes
L R
LR
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology; D051379:Mice; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D005493:Folic Acid Antagonists; D011799:Quinazolines; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase