Quinazoline-2,4(1H, 3H)-diones inhibit the growth of multiple human tumor cell lines.
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.
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.
Xiaoli
X
Zhou
Xilei
X
Xie
Gang
G
Liu
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D052999:Quinazolinones