EZH2甲基转移酶抑制剂的设计、合成及其抑制活性

对2-(3-甲基-6-甲氧基喹唑啉-2-氨基)-6-(1-苯基-1H-四唑-5-硫甲基)-4-嘧啶酮(DCE-254)进行了分子对接,设计、合成了14个DCE-254类似物。以4-氯乙酰乙酸乙酯、1-苯基-5-巯基四氮唑、盐酸胍、取代苯甲酰氯、取代异硫氰酸酯等为原料,合成了这些类似物Ⅴa～Ⅵh。采用MS、1HNMR和13CNMR对这些类似物的结构进行了表征。H3K27me放射性甲基化抑制测试得到了5个具有较强甲基化抑制作用的DCE-254类似物,活性最好的是N-[4-羟基-6-(1-苯基-1H-四氮唑-5-硫甲基)-2-嘧啶]-N′-2-甲氧基-5-甲基苯基硫脲(Ⅵf),其甲基化抑制率达到77%,优于DCE-254的70%。     

酪氨酸激酶抑制剂的合成及抗肿瘤活性

以4-氯-6,7-二甲氧基喹唑啉、8-溴辛酸乙酯及溴代正丁烷等为原料,根据喹唑啉类化合物药效结构关系,对N-(3-氯-4-烷氧苯基)喹唑啉-4-胺类化合物(ARRY-334543)进行了结构修饰,合成了具有抗肿瘤细胞活性的酪氨酸激酶抑制剂(Ⅷa~c、Ⅸa和Ⅸb)。采用NMR和MS对抑制剂的结构进行了表征,并对其进行了抗肿瘤细胞活性测试。得到的化合物Ⅸa和Ⅸb均对MCF-7、BGC-823、A549、DU145和H1975细胞有一定的抗肿瘤活性,其中,活性最好的是化合物Ⅸa,其对MCF-7细胞的半数抑制浓度(GI50)为0.37μmol/L。     

多取代吡啶酮衍生物的设计、合成及对DPP-Ⅳ蛋白酶的抑制活性

通过分析alogliptin与DPP-Ⅳ蛋白酶的构效关系,通过骨架跃迁以及官能团互换,设计并合成出15个多取代吡啶酮类化合物,通过1HNMR和质谱确定了它们的结构,并对其进行了初步的体外酶活性筛选,得到了3个化合物11a、38、41与alogliptin活性相当的化合物,初步确立了该类化合物的DPP-Ⅳ酶构效关系。     

芳香基苦参碱衍生物的合成及抗肿瘤活性

分别以茴香醛、黎芦醛、3,4,5-三甲氧基苯甲醛、2,3,4-三甲氧基苯甲醛为原料,在氢化钠的作用下,与苦参碱发生Claisen-Schimidt缩合反应合成了4个芳香基苦参碱衍生物;采用MTT法测试目标化合物对人结肠癌细胞株HT-29,人胰腺癌细胞株PANC-1的增殖抑制活性。结果表明,合成的芳香基苦参碱衍生物的IC50值分别为27.8、18.0、9.05、13.2μmol/L,苦参碱的IC50值为28.6μmol/L,4个苦参碱衍生物的抗肿瘤活性较苦参碱有所提高。     

新型蛋白质精氨酸甲基转移酶抑制剂的合成

为了研究蛋白质精氨酸甲基转移酶的抑制作用,设计并合成了标题化合物。此化合物的合成是通过卤化、取代、胍基化和脱保护基4步反应,其结构经1HNMR、13CNMR和MS表征。     

苯乙烯喹啉衍生物的合成及抗癌活性

以取代的苯胺和反式丁烯醛为原料,在盐酸中反应得到4个2-甲基喹啉衍生物,所得产物再与芳香醛在冰醋酸中回流反应合成了10个苯乙烯喹啉衍生物,收率为64%~78%。所得化合物的结构经1HNMR、MS、IR表征确认,并采用MTT法进行初步体外抗肿瘤活性筛选。结果表明,化合物Ⅱc对A 549和HCT 116细胞均有较高的抑制活性,IC50值分别为9.77和9.66μmol/L,化合物Ⅱd对HCT 116细胞有较高的抑制活性,IC50值为9.80μmol/L。     

新型双酰胺衍生物的合成及抗癌活性

以取代苯甲酸为起始原料,设计合成了10个含苯并噻唑基双酰胺类化合物,其结构经1HNMR、13CNMR、IR及元素分析确证。采用MTT法进行化合物抑制PC3、BGC-823癌细胞体外活性测试,结果表明,所合成的化合物具有不同程度地抑制癌细胞活性,其中化合物N-[2-(6-甲基苯并噻唑-2-氨基甲酰基)-4-甲基苯基]-4-氯苯甲酰胺(Ⅳa)和N-[2-(4-甲基苯并噻唑-2-氨基甲酰基)-4-甲基苯基]-2-甲基苯甲酰胺(Ⅳe)在10μmol/L浓度下对PC3的抑制率为70.8%和68.4%,N-[2-(苯并噻唑-2-氨基甲酰基)-4-甲基苯基]-2-甲基苯甲酰胺(Ⅳd)在10μmol/L浓度下对BGC-823的抑制率为65.9%。     

两个Galaxamide类似物的合成及其抗肿瘤活性初探

以D-苯丙氨酸和D-亮氨酸为起始原料,采用液相合成法,经典的"3+2"合成策略,通过对氨基酸N端的保护及脱保护、C端的脱保护、氨基酸的甲基化、缩合等步骤,以混合缩合试剂DEPBT/HATU/TBTU关环,合成了两个环五肽HW-1和HW-2,化合物结构通过1HNMR,13CNMR,MS和ICP-MS进行表征。采用MTT法对目标产物HW-1和HW-2进行抗肿瘤活性筛选,结果显示其具有良好的活性,尤其对Hep G2的IC50值分别为3.14和9.2 mg/L。     

5-氟尿嘧啶甘氨酸类化合物的合成、表征及抗癌活性

常温下,以5-氟尿嘧啶为起始原料,以1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDCI)和1-羟基苯并三氮唑(HOBt)为缩合剂,通过液相偶联法,合成了2-(5-氟尿嘧啶-1-基乙酰基)氨基乙酸甲酯,收率72%;控制pH=10～11,温度20～30℃水解得到相应的2-(5-氟尿嘧啶-1-基乙酰基)氨基乙酸,收率75%。两个化合物的结构通过1HNMR、13CNMR、MS、IR确证;通过紫外吸收光谱初步揭示了化合物的抗肿瘤机制;委托国家新药筛选中心进行了体外抗白血病细胞株HL-60和肝癌细胞株BEL-7402活性测试,结果表明,该化合物具有一定的体外抑制肿瘤作用。     

醋酸羟丙基甲基纤维素琥珀酸酯的合成

以羟丙基甲基纤维素(HPMC)为原料,琥珀酸酐、乙酸酐为酯化剂,在醋酸中进行酯化反应制备了醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)。通过改变影响基团质量分数的各种因素条件,得到了不同取代度的产物。采用滴定法测定了琥珀酰基、乙酰基的质量分数,并对产品结构进行表征和性能测试。结果表明,该反应体系在105℃反应6.5 h,反应后选用去离子水为沉淀剂,机械搅拌(750 r/min)使产物沉析,可得到琥珀酰基和乙酰基质量分数分别为13%和8%左右的产品。获得的产品HPMCAS多分散系数为1.06,相对分子质量(简称分子量,下同)分布较窄,在丙酮、甲醇等溶剂中表现出良好的溶解性能,并在200℃前对热稳定。     

Design, synthesis and biological evaluation of sugar-derived Ras inhibitors

The design and synthesis of novel Ras inhibitors with a bicyclic scaffold derived from the natural sugar D-arabinose are presented. Molecular modelling showed that these ligands can bind Ras by accommodating the aromatic moieties and the phenylhydroxylamino group in a cavity near the Switch II region of the protein. All the synthetic compounds were active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibited Ras-dependent cell growth in vivo.     

Design, synthesis, and biological evaluation of 2-aminobenzanilide derivatives as potent and selective HDAC inhibitors

Epigenetic regulation is an essential process for the normal functioning of genes. Therefore, targeting epigenetic dysregulation in cancer may be a valid therapeutic approach for the treatment of this severe disease. Histone deacetylases (HDACs) are enzymes involved in the regulation of epigenetic post-translational modifications; because they are overexpressed in many types of cancer, HDACs are valuable targets for the development of new anticancer agents. A large series of 2-aminobenzanilides linked at the 4'-position to α-amino acid amides, arenes, and heteroarenes through a methylene bridge were designed, synthesized, and tested as novel HDAC inhibitors. Several compounds showed IC(50) values in the two-digit nanomolar range in hrHDAC1 inhibition assays, lower than that of the reference compound MS-275. They also showed interesting selectivity profiles, as confirmed by western blot assays.     

微波辐射下1,2,4-三唑硫酮席夫碱的合成及表征

微波辐射条件下,以氨基均三唑硫醇与查尔酮为原料,通过亲核取代反应,制备了3-(4-氨基-5-硫基-3-苯基均三唑-1-氮代)-1,3-二苯-1-丙酮(Ⅳ),Ⅳ与系列芳香醛经缩合反应,合成了7种三唑硫酮席夫碱Ⅴa～Ⅴg。探讨了原料摩尔比、催化剂用量、反应时间、溶剂、微波辐射功率对收率的影响,得到了优化的工艺条件:n(芳香醛)∶n(氨基三唑硫酮)=1∶1.1,微波功率500 W,催化剂冰醋酸2 mL,反应时间5～7 min,溶剂为N,N-二甲基甲酰胺(DMF),收率为71%～87%。用IR、MS、1HNMR、元素分析对合成中间体和目标产物进行了结构表征。     

Discovery of a Non-Nucleoside SETD2 Methyltransferase Inhibitor against Acute Myeloid Leukemia

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and cell differentiation. Here, we describe the identification of first-generation cell-permeable non-nucleoside type inhibitors of SETD2, the only mammalian HMT that is able to tri-methylate the K36 residue of histone H3. By generating the epigenetic mark H3K36me3, SETD2 is involved in the progression of acute myeloid leukemia. We developed a structure-based virtual screening protocol that was first validated in retrospective studies. Next, prospective screening was performed on a large library of commercially available compounds. Experimental validation of 22 virtual hits led to the discovery of three compounds that showed dose-dependent inhibition of the enzymatic activity of SETD2. Compound C13 effectively blocked the proliferation of two acute myeloid leukemia (AML) cell lines with MLL rearrangements and led to decreased H3K36me3 levels, prioritizing this chemotype as a viable chemical starting point for drug discovery projects.     

Design, synthesis, and biological activity of hydroxamic tertiary amines as histone deacetylase inhibitors

Herein we describe the design, synthesis, and biological evaluation of new hydroxamic tertiary amines as histone deacetylase (HDAC) inhibitors. These compounds have allowed us to clarify the influence of cap group dimension and hydrophobicity on HDAC inhibitory activity. This report also reveals the recognition pattern between the linear compounds and the histone deacetylase-like protein (HDLP) model receptor, and discusses the synthesis and in vitro evaluation of HDAC inhibitory activity in HeLa cell nuclear extracts. We obtained good qualitative agreement between experimental results and theoretical predictions, confirming that appropriately substituted hydroxamic tertiary amines are potential active HDAC inhibitors.     

Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors

In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.     

硒化二氢杨梅素的制备及抗肿瘤活性

以DMY为基底物、Na2SeO3为硒化剂制备硒化DMY。采用UV、FTIR、NMR、XRD、TG、原子荧光光度计表征其结构和性能，CCK-8法检测对HSC-3细胞增殖的影响，划痕实验研究对HSC-3细胞迁移的影响。结果表明，硒化DMY中仍存在黄酮基本母核、并新形成C-Se键，其中硒含量为6.54%±0.22%；DMY和硒化DMY均对HSC-3细胞的增殖和迁移有良好的抑制作用、抑制效果与浓度呈正相关，且DMY和硒化DMY对HSC-3细胞的半数抑制浓度（IC50）分别为25.27 μg/mL、21.27 μg/mL，DMY的硒化有效提高了对HSC-3细胞增殖和迁移的抑制能力。     

离子液体催化2-氯噻吩氯甲基化反应研究

以2-氯噻吩、多聚甲醛为原料,以离子液体[C2mim]Br、[C3mim]Br、[C4mim]Br、[C5mim]Br、[C6mim]Br、[C7mim]Br、[C8mim]Br、[C12mim]Br、[Bmim]PF6、[Bmim]BF4、[Bmim]C4F9SO3和[Bmim]Cl为催化剂进行氯甲基化反应,得到产物2-氯-3-氯甲基噻吩。研究表明,离子液体可以促进2-氯噻吩的氯甲基化反应,具有相转移催化剂的效果,并且以[C4mim]Br和[C8mim]Br的催化效果为佳。反应最佳条件为:离子液体[C8mim]Br摩尔分数为5%(相对于2-氯噻吩),温度40℃,反应时间8h,产物产率可达92.1%。