Marsham P R, Chambers P, Hayter A J, Hughes L R, Jackman A L, O'Connor B M, Bishop J A, Calvert A H
ICI Pharmaceuticals, Macclesfield, Cheshire, England.
J Med Chem. 1989 Mar;32(3):569-75. doi: 10.1021/jm00123a010.
The synthesis of 16 new N10-propargylquinazoline antifolates with methylamino, ethylamino, (2-aminoethyl)amino, [2-(dimethylamino)ethyl]amino, (2-hydroxyethyl)amino, (carboxymethyl)amino, dimethylamino, imidazol-1-yl, methoxy, ethoxy, phenoxy, 2-methoxyethoxy, 2-hydroxyethoxy, mercapto, methylthio, and chloro substituents at C2 is described. In general, the synthetic route involved the coupling of diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate (5a) with 6-(bromomethyl)-2-chloro-3,4-dihydro-4-oxoquinazoline in N,N-dimethylformamide with calcium carbonate as the base, displacement of the C2-chloro substituent with nitrogen and sulfur nucleophiles, and deprotection using mild alkali. The C2-ether analogues were most conveniently prepared by coupling 5a with 6-(bromomethyl)-2,4-diakoxy(or diphenoxy)quinazolines. In this series the final deprotection step with aqueous alkali gave simultaneous selective hydrolysis of the C4-alkoxy or C4-phenoxy substituent. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). As a measure of cytotoxicity, they were examined for their inhibition of the growth of L1210 cells in culture. The C2-methoxy analogue 11a was equivalent to the previously described tight binding TS inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717, ICI 155387, 1a) against the TS enzyme and exhibited enhanced potency in culture. The C2-methoxy substituent also gave a 110-fold enhancement in aqueous solubility relative to the C2-amine. These results suggest that 11a will be an interesting compound for further study as a potential antitumor agent in vivo. A further series of 2-methoxyquinazoline antifolates with modified alkyl substituents at N10 is also described. None of these analogues equalled the activity of 11a. Thus the propargyl group appears to be the optimum N10 substituent in both 2-amino- and 2-methoxyquinazoline antifolates.
描述了16种新的N10-炔丙基喹唑啉抗叶酸剂的合成，这些抗叶酸剂在C2位带有甲氨基、乙氨基、（2-氨基乙基）氨基、[2-（二甲氨基）乙基]氨基、（2-羟乙基）氨基、（羧甲基）氨基、二甲氨基、咪唑-1-基、甲氧基、乙氧基、苯氧基、2-甲氧基乙氧基、2-羟乙氧基、巯基、甲硫基和氯取代基。一般来说，合成路线包括在N，N-二甲基甲酰胺中，以碳酸钙为碱，使N-[4-（丙-2-炔基氨基）苯甲酰基]-L-谷氨酸二乙酯（5a）与6-（溴甲基）-2-氯-3，4-二氢-4-氧代喹唑啉偶联，用氮和硫亲核试剂取代C2-氯取代基，并用温和的碱进行脱保护。C2-醚类似物最方便的制备方法是将5a与6-（溴甲基）-2，4-二烷氧基（或二苯氧基）喹唑啉偶联。在该系列中，用水性碱进行的最终脱保护步骤同时导致C4-烷氧基或C4-苯氧基取代基的选择性水解。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。作为细胞毒性的一种衡量指标，检测了它们对培养的L1210细胞生长的抑制作用。C2-甲氧基类似物11a对TS酶的活性与先前描述的紧密结合TS抑制剂N10-炔丙基-5，8-二去氮叶酸（CB3717，ICI 155387，1a）相当，并且在培养中表现出增强的效力。相对于C2-胺，C2-甲氧基取代基还使水溶性提高了110倍。这些结果表明，11a作为一种潜在的体内抗肿瘤剂将是一种值得进一步研究的有趣化合物。还描述了另一系列在N10位带有修饰烷基取代基的2-甲氧基喹唑啉抗叶酸剂。这些类似物均未达到11a的活性。因此，炔丙基似乎是2-氨基和2-甲氧基喹唑啉抗叶酸剂中最佳的N10取代基。
