中科院上海药物研究所柳红研究员课题组与蒙凌华研究员合作，设计并合成了一系列结构新颖的稠环类氨基硫脲衍生物，并对该系列化合物的抗肿瘤活性和作用机制进行了深入研究。
缩氨基硫脲类化合物因其具有广泛的生物活性，如抗病毒、抗细菌、抗真菌、抗肿瘤活性而引起医药工作者的重视。
多个化合物能够显著抑制HL-60、SGC-7901、Hela和HT-29人肿瘤细胞的增殖，其中化合物TSC24活性最强。TSC24对22种不同细胞株增殖抑制的IC50值处于2 nM到830 nM之间，其中对Rh30细胞增殖抑制的IC50值为2 nM。此外，TSC24对人癌裸小鼠移植瘤的生长也表现出显著的抑制活性。
据报道，缩氨基硫脲类化合物具有铁螯合作用，从而阻断含铁的核苷酸还原酶，使DNA合成受阻。研究表明化合物TSC24具有明显的铁螯合作用，但增加铁离子仅能部分抵消TSC24的药效，因此推测其还具有其他抗肿瘤机理。通过COMPARE分析提示DNA拓扑异构酶II（TopoII）可能是缩氨基硫脲类化合物作用靶点。进一步的研究发现TSC24是一个Topo IIα催化抑制剂，并能够抑制Topo II毒剂VP16诱导的DNA双螺旋断裂。
TSA24通过与 ATP竞争性地结合与人Tope IIα ATP酶域结合，抑制TopoII催化的ATP水解，从而阻断Topo II催化循环。此项研究结果对开发新一代硫脲类抗肿瘤化合物和Topo II抑制剂有一定借鉴和指导意义。
该研究项目得到了国家自然科学基金委及863项目的资助。相关成果发表于最新一期的美国《药物化学杂志》。
推荐原文出处：
J. Med. Chem. DOI: 10.1021/jm901783v
Synthesis and SAR of Novel 4-Morpholinopyrrolopyrimidine Derivatives as Potent Phosphatidylinositol 3-Kinase Inhibitors
Zecheng Chen*, Aranapakam M. Venkatesan, Christoph M. Dehnhardt, Semiramis Ayral-Kaloustian, Natasja Brooijmans, Robert Mallon, Larry Feldberg, Irwin Hollander, Judy Lucas, Ker Yu, Fangming Kong§ and Tarek S. Mansour
Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110α isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kα and mTOR, leading to the discovery of PI3Kα selective inhibitors (e.g., 9) and dual PI3Kα/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kα/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
