中科院上海藥物研究所柳紅研究員課題組與蒙凌華研究員合作，設(shè)計(jì)并合成了一系列結(jié)構(gòu)新穎的稠環(huán)類(lèi)氨基硫脲衍生物,，并對(duì)該系列化合物的抗腫瘤活性和作用機(jī)制進(jìn)行了深入研究,。
縮氨基硫脲類(lèi)化合物因其具有廣泛的生物活性，如抗病毒,、抗細(xì)菌,、抗真菌、抗腫瘤活性而引起醫(yī)藥工作者的重視,。
多個(gè)化合物能夠顯著抑制HL-60,、SGC-7901,、Hela和HT-29人腫瘤細(xì)胞的增殖，其中化合物TSC24活性最強(qiáng),。TSC24對(duì)22種不同細(xì)胞株增殖抑制的IC50值處于2 nM到830 nM之間,，其中對(duì)Rh30細(xì)胞增殖抑制的IC50值為2 nM。此外,，TSC24對(duì)人癌裸小鼠移植瘤的生長(zhǎng)也表現(xiàn)出顯著的抑制活性,。
據(jù)報(bào)道，縮氨基硫脲類(lèi)化合物具有鐵螯合作用,，從而阻斷含鐵的核苷酸還原酶,，使DNA合成受阻。研究表明化合物TSC24具有明顯的鐵螯合作用,，但增加鐵離子僅能部分抵消TSC24的藥效,，因此推測(cè)其還具有其他抗腫瘤機(jī)理。通過(guò)COMPARE分析提示DNA拓?fù)洚悩?gòu)酶II（TopoII）可能是縮氨基硫脲類(lèi)化合物作用靶點(diǎn),。進(jìn)一步的研究發(fā)現(xiàn)TSC24是一個(gè)Topo IIα催化抑制劑,，并能夠抑制Topo II毒劑VP16誘導(dǎo)的DNA雙螺旋斷裂。
TSA24通過(guò)與 ATP競(jìng)爭(zhēng)性地結(jié)合與人Tope IIα ATP酶域結(jié)合,，抑制TopoII催化的ATP水解,，從而阻斷Topo II催化循環(huán)。此項(xiàng)研究結(jié)果對(duì)開(kāi)發(fā)新一代硫脲類(lèi)抗腫瘤化合物和Topo II抑制劑有一定借鑒和指導(dǎo)意義,。
該研究項(xiàng)目得到了國(guó)家自然科學(xué)基金委及863項(xiàng)目的資助,。相關(guān)成果發(fā)表于最新一期的美國(guó)《藥物化學(xué)雜志》。
生物谷推薦原文出處：
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.
