Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors.
The synthesis is described of a series of analogues of the potent thymidylate synthase (TS) inhibitor, N-[4-[N-[(3,4-dihydro-2, 7-dimethyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]-2-f luorob enzoyl]-L-glutamic acid (4, ZM214888), in which the glutamic acid moiety is replaced by homologous amino acids and alpha-amino acids where the omega-carboxylate is replaced by acylsulfonamides and acidic heterocycles. In general these modifications when compared to 4 gave compounds with increased potency as inhibitors of isolated TS and as cytotoxic agents against murine tumor cell lines. The new compounds require transport by the reduced folate carrier for entry into cells but are not converted intracellularly into polyglutamated species. Agents with this profile are expected to show activity against tumors that are resistant to classical antifolates due to low expression of folylpolyglutamate synthetase. The analogue (S)-2-[4-[N-[(3,4-dihydro-2, 7-dimethyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]-2-f luorob enzamido]-4-(1H-1,2,3,4-tetrazol-5-yl)butyric acid (35, ZD9331) has been selected as a clinical development candidate and is currently undergoing phase I studies.
Marsham
P R
PR
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, England.
Wardleworth
J M
JM
Boyle
F T
FT
Hennequin
L F
LF
Kimbell
R
R
Brown
M
M
Jackman
A L
AL
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology; D051379:Mice; D008956:Models, Chemical; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; C094299:ZD 9331; D013940:Thymidylate Synthase