摘要
CPS11无论在体外活性评价还是在体内的药效学评价中,都表现出很高的抗肿瘤生长活性和抑制血管新生活性。但CPS11难以制备得到高纯度的产品,并且在放置过程中极其不稳定。因此,CPS11难以开发成临床上可用的药物。基于此,我们合成了一系列CPS11的前药,通过溶液稳定性研究、溶解度研究、动物体内/体外代谢研究、动物组织分布研究和体内/体外药效学评价筛选得到化合物Ⅱ。
化合物Ⅱ可制备成有机酸盐或无机酸盐,提高了化合物在水中的溶解度。化合物Ⅱ在溶液中的稳定性较CPS11大大提高。并且化合物Ⅱ在放置一年半后,HPLC测试显示纯度没有明显变化。化合物Ⅱ在动物体内可迅速代谢出活性物质CPS11和沙利度胺。化合物Ⅱ具有较好的生物利用度,小鼠灌胃给药和腹腔给药的生物利用度分别为60.7%和79.5%。化合物Ⅱ在体外不同生物样品中具有类似的代谢模式,可避免不同种属代谢差异而导致的活性或毒性差异,且引入基团为内源性的物质-烟酸,可降低或避免由于引入基团可能产生的毒副作用。
体外活性评价结果表明化合物Ⅱ能够显著抑制ECV-304细胞的增殖活性,IC50为0.143μM;化合物Ⅱ在195μM的浓度下对人脐静脉内皮细胞小管形成抑制为91.9%。在鼠源黑色素瘤B16肺转移模型中,化合物Ⅱ能够显著抑制B16在动物肺部形成转移灶,抑制率为74%,并且对动物没有显著的毒性作用。在鼠源脑胶质瘤G422皮下肿瘤模型的药效实验中,化合物Ⅱ与BCNU联合用药组抑瘤率为71.14%,CDI为0.58;表明化合物Ⅱ与BCNU联合应用具有协同抑制肿瘤生长的作用。在人源乳腺癌MX-1裸鼠异体移植瘤模型中,化合物Ⅱ联合紫杉醇对肿瘤的生长抑制率为74.3%,CDI为0.4,体现出显著的协同作用,并且没有出现毒性的协同或相加作用。
通过对化合物Ⅱ的一系列评价,化合物Ⅱ具备开发成药物的潜力。
CPS11 significantly inhibited angiogenesis and tumor growth, both in vitro and in vivo. CPS11 can not be obtained with high purity and unstable during storage. Therefore, prodrugs of CPS11 are synthesized, and compound I and compoundⅡare chosen for efficacy study.
CompoundⅡcan form salt with organic acid or inorganic acid. The stability of compoundⅡis significantly increased, and after one and half years the purity of compoundⅡis same as the initial purity. In pharmacokinetics study of compoundⅡ, after 1 min, only the active metabolite thalidomide and CPS11 could be detected following i.v. administration of compoundⅡ. CompoundⅡhas good bioavailability. The bioavailabilities in mice are 60.7% and 79.5% respectively after intragastric administration or intraperitoneal injection with CompondⅡ.
In vitro, compoundⅡcan significantly inhibit ECV-304 cell growth, and the IC50 is 0.143μM. In Tube formation, significant inhibition is observed with CompoundⅡand the inhibition is 91.9%. In vivo, compoundⅡcould enhance antitumor efficacy of Taxol on MX-1 human breast cancer xenograft model, and the CDI is 0.4. CompoundⅡcan enhance antitumor efficacy of BCNU on G422 mouse glioma cancer model, and the CDI is 0.58. CompoundⅡcan significantly inhibit the metastasis of B16 murine melanoma and the inhibition is 74%.
These results warrant further evaluation of compound I and compoundⅡas novel anti-cancer agents.
引文
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