Smaill J B, Palmer B D, Rewcastle G W, Denny W A, McNamara D J, Dobrusin E M, Bridges A J, Zhou H, Showalter H D, Winters R T, Leopold W R, Fry D W, Nelson J M, Slintak V, Elliot W L, Roberts B J, Vincent P W, Patmore S J
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
J Med Chem. 1999 May 20;42(10):1803-15. doi: 10.1021/jm9806603.
A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.
通过使相应的氨基化合物与丙烯酰氯/碱或丙烯酸/1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐反应，制备了一系列表皮生长因子受体(EGFR)抑制剂的4-(苯氨基)喹唑啉和吡啶并嘧啶类的6-和7-丙烯酰胺衍生物。所有的6-丙烯酰胺，但只有母体喹唑啉7-丙烯酰胺，是分离酶的不可逆抑制剂，这证实了前者在与酶结合时，与关键的半胱氨酸-773反应的位置更佳。喹唑啉、吡啶并[3,4-d]嘧啶和吡啶并[3,2-d]嘧啶6-丙烯酰胺都是不可逆抑制剂，并且在酶分析中显示出相似的高效力(可能是由于对可用酶的滴定)。然而，在A431细胞中EGFR的细胞自磷酸化分析中，吡啶并[3,2-d]嘧啶类似物的效力比其他类似物低2至6倍。喹唑啉总体上对抑制heregulin刺激的erbB2自磷酸化(在MDA-MB-453细胞中)的效力通常较低，而吡啶并嘧啶则具有同等效力。对选定的化合物在A431表皮样和H125非小细胞肺癌人肿瘤异种移植模型中进行了评估。这些化合物口服给药时比腹腔注射显示出更好的活性。在一定剂量范围内，所有化合物均显示出显著的肿瘤生长抑制(停滞)。这些化合物较差的水溶性是一个缺点，需要配制成细颗粒乳液。
