Design, Synthesis, and Preclinical Evaluation of New 5,6- (or 6,7-) Disubstituted-2-(fluorophenyl)quinolin-4-one Derivatives as Potent Antitumor Agents
Design, Synthesis, and Preclinical Evaluation of New 5,6- (or 6,7-) Disubstituted-2-(fluorophenyl)quinolin-4-one Derivatives as Potent Antitumor Agents
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DOI：
10.1021/jm100780c
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发表时间：
2010-11-25
影响因子：
7.3
通讯作者：
Kuo, Sheng-Chu
中科院分区：
文献类型：
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作者：
Chou, Li-Chen;Tsai, Meng-Tung;Kuo, Sheng-Chu
我们先前对2-苯基喹啉-4-酮（2-PQs）的探索导致了抗癌药物候选物2-（2-氟苯基）-6，7-亚甲二氧基喹啉-4-酮双磷酸盐（CHM-1-P-Na）。为了开发额外的新候选药物，设计、合成新型2-PQ，并评价其细胞毒性活性。大多数类似物，包括1B、2a、B、3a、B、4a、B和5a、B，对所有测试的肿瘤细胞系表现出显著的抑制活性（IC 50为0.03-8.2 μ M）。作为最有效的类似物之一，2-（3-氟苯基）-5-羟基-6-甲氧基喹啉-4-酮（3b）在美国国家癌症研究所（NCI）的评估中选择性地抑制60种癌细胞系中的14种。初步的作用机制研究表明，3b对胰岛素样生长因子-1受体（IGF-1 R）的酪氨酸自磷酸化有显著影响。安全药理学特征3b显示对大多数检测酶的正常生物学功能无显著影响。此外，2-（3-氟苯基）-6-甲氧基-4-氧代-1，4-二氢喹啉-5-基磷酸钠（15）（3b的单磷酸盐）超过多柔比星的活性，并且在Hep 3B异种移植裸鼠模型中与CHM-1-P-Na相当。总之，15是一个有前途的临床候选药物，目前正在进行临床前研究。
Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC50 of 0.03-8.2 mu M) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.