Marsham P R, Jackman A L, Oldfield J, Hughes L R, Thornton T J, Bisset G M, O'Connor B M, Bishop J A, Calvert A H
ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, England.
J Med Chem. 1990 Nov;33(11):3072-8. doi: 10.1021/jm00173a026.
The synthesis of nine new 2-methyl-10-propargylquinazoline antifolates with substituents in the p-aminobenzoyl ring is described. In general the synthetic route involved the coupling of the appropriate ring-substituted diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate with 6-(bromomethyl)-3,4-dihydro-2-methyl-4-oxoquinazoline followed by deprotection using mild alkali. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth L1210 cells in culture. Compared to the parent compound 1a the 2'-fluoro analogue 2a exhibited enhanced potency in both systems whereas the 3'-fluoro analogue 3a showed enhanced growth inhibitory properties against L1210 cells despite being a poorer inhibitor of the isolated enzyme. Chloro, hydroxy, methoxy, and nitro substituents in the 2'-position were also well tolerated by the enzyme but failed to give enhanced growth inhibition. The series was extended to cover analogues of the 2'-fluoro, 3'-fluoro, 2'-chloro, 2'-methyl, 2'-amino, 2'-methoxy, and 2'-nitro derivatives with modified alkyl substituents at N10.
本文描述了九种新的2-甲基-10-炔丙基喹唑啉抗叶酸剂的合成，这些抗叶酸剂在对氨基苯甲酰环上带有取代基。一般来说，合成路线包括将适当的环取代的N-[4-(丙-2-炔基氨基)苯甲酰基]-L-谷氨酸二乙酯与6-(溴甲基)-3,4-二氢-2-甲基-4-氧代喹唑啉偶联，然后用温和的碱进行脱保护。测试了这些化合物作为部分纯化的L1210胸苷酸合成酶（TS）抑制剂的活性。还检测了它们对培养的L1210细胞生长的抑制作用。与母体化合物1a相比，2'-氟类似物2a在两个系统中均表现出增强的效力，而3'-氟类似物3a尽管对分离的酶的抑制作用较差，但对L1210细胞显示出增强的生长抑制特性。2'-位的氯、羟基、甲氧基和硝基取代基也能被该酶很好地耐受，但未能增强生长抑制作用。该系列扩展到涵盖在N10处具有修饰烷基取代基的2'-氟、3'-氟、2'-氯、2'-甲基、2'-氨基、2'-甲氧基和2'-硝基衍生物的类似物。
