Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
J Med Chem. 2010 Feb 25;53(4):1616-26. doi: 10.1021/jm901292j.
CHM-1 [2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one] (1) has a unique antitumor mechanism of action. However, because 1 has relatively low hydrophilicity, it was evaluated only via ip administration, which is not clinically acceptable. In this study, we synthesized the monosodium phosphate salt (CHM-1-P-Na, 4) of 1 as a hydrophilic prodrug. Compound 4 was rapidly converted into 1 following iv and po administration and also possessed excellent antitumor activity in a SKOV-3 xenograft nude mice model. Compound 4 also had clear-cut pharmacological effects on enzymes related with tumor cells. Neither 4 nor 1 significantly affected normal biological function in a safety pharmacology profiling study. Compound 1 caused apoptotic effects in breast carcinoma cells via accumulation of cyclin B1, and importantly, the endogenous levels of the mitotic spindle checkpoint proteins BubR1 directly correlated with cellular response to microtubule disruption. With excellent antitumor activity profiles, 4 is highly promising for development as an anticancer clinical trials candidate.
CHM-1 [2-(2-氟苯基)-6,7-亚甲二氧基喹啉-4-酮]（1）具有独特的抗肿瘤作用机制。然而，由于 1 的亲水性相对较低，仅通过 ip 给药进行了评估，这在临床上是不可接受的。在本研究中，我们合成了 1 的单磷酸钠盐（CHM-1-P-Na，4）作为亲水性前药。化合物 4 在 iv 和 po 给药后迅速转化为 1，并且在 SKOV-3 异种移植裸鼠模型中具有优异的抗肿瘤活性。化合物 4 对与肿瘤细胞相关的酶也具有明显的药理作用。在安全性药理学分析研究中，4 和 1 均未对正常的生物学功能产生显著影响。化合物 1 通过 cyclin B1 的积累对乳腺癌细胞产生凋亡作用，重要的是，有丝分裂纺锤体检查点蛋白 BubR1 的内源性水平与细胞对微管破坏的反应直接相关。4 具有优异的抗肿瘤活性特征，非常有希望作为抗癌临床试验候选药物进行开发。
