Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Road, Xuanwu District, Beijing 100050, People's Republic of China.
Mol Divers. 2013 May;17(2):197-219. doi: 10.1007/s11030-012-9421-y. Epub 2013 Jan 26.
Quinazoline-2,4(1H, 3H)-diones exhibit a wealth of biological activities including antitumor proliferation. We established an improved method for the synthesis of quinazoline-2,4(1H, 3H)-dione derivatives with three points of molecular diversity. Data indicate that compounds 60 (average logGI50=−6.1), 65 (average logGI50=−6.13), 69 (average logGI50 = −6.44), 72 (average logGI50 = −6.39), and 86 (average logGI50 = −6.45) significantly inhibited the in vitro growth of 60 human tumor cell lines tested. Structure–activity relationship analyses indicate that chlorophenethylureido is the necessary substituent at the D3 diversity point (7-position of quinazoline-2,4(1H, 3H)-dione), in particular, o-chlorophenethylurea (69) achieved optimal activity. o- or m-Chlorophenethyl substitutions (69 and 72) at the D2 diversity point (3-position of quinazo line-2,4(1H, 3H)-dione) gave the most potent compounds. Methoxyl and 4-methylpiperazin-1-yl substitution at the D1 diversity point (6-position of quinazoline-2,4(1H, 3H)-dione skeleton) may yield better activity than other groups. The quinazoline-2,4(1H, 3H)-dione scaffold can be effectively replaced by 2H-benzo[b][1,4]thiazin-3(4H)-one.
喹唑啉-2,4(1H,3H)-二酮具有丰富的生物活性，包括抗肿瘤增殖。我们建立了一种改进的方法，用于合成具有三点分子多样性的喹唑啉-2,4(1H,3H)-二酮衍生物。数据表明，化合物 60（平均 logGI50=-6.1）、65（平均 logGI50=-6.13）、69（平均 logGI50=-6.44）、72（平均 logGI50=-6.39）和 86（平均 logGI50=-6.45）显著抑制了 60 个人类肿瘤细胞系的体外生长。构效关系分析表明，D3 多样性点（喹唑啉-2,4(1H,3H)-二酮的 7 位）的必要取代基是氯苯乙基脲基，特别是邻氯苯乙基脲（69）获得了最佳活性。D2 多样性点（喹唑啉-2,4(1H,3H)-二酮的 3 位）的邻氯或间氯苯乙基取代（69 和 72）给出了最有效的化合物。D1 多样性点（喹唑啉-2,4(1H,3H)-二酮骨架的 6 位）的甲氧基和 4-甲基哌嗪-1-基取代可能比其他基团产生更好的活性。2H-苯并[b][1,4]噻嗪-3(4H)-酮可以有效地替代喹唑啉-2,4(1H,3H)-二酮支架。
