新型鬼臼毒素衍生物的合成及其抗肿瘤活性

目的 设计并合成新型鬼臼毒素类衍生物。方法 5-甲氧基吲哚与氯代物或酰氯反应得到一位氮取代的5-甲氧基吲哚;其与草酰氯反应,再以4-氨基4-脱氧表鬼臼毒素为原料,经缩合反应得到目标化合物。体外活性采用Hela细胞筛选模型进行评价。结果与结论 合成了7个新化合物,其中化合物7a, 7b 的活性优于阳性对照依托泊苷（etoposide）。     

鬼臼毒素衍生物的合成及其体外抗肿瘤活性

目的 获得更高活性且具有抗多药耐药活性的抗肿瘤新化合物。方法 将4β-氨基-4-脱氧鬼臼毒素与醇类化合物以丁二酸为桥连接合成了7个鬼臼毒素衍生物,其结构经1H-NMR、TOF-MS证实。用K562和K562/AO2细胞经MTT法筛选了这些衍生物的体外抗肿瘤活性。结果 7个化合物均为新化合物,其中5b、5d的抗肿瘤活性显著高于VP-16, 并且5b、5c、5d、5e的抗多药耐药活性显著高于VP-16。结论 这些鬼臼毒素衍生物可提高抗肿瘤活性。     

表鬼臼毒素羧酸酯的合成及体外抗肿瘤活性

在三氟化硼·乙醚的催化作用下,鬼臼毒素(I)与有机酸直接脱水生成了具有4β-构型的表鬼臼毒素羧酸酯(IIa～g),所有合成产物经IR,¹HNMR,MS和元素分析等确证其结构,初步药理试验表明,该类化合物对小鼠白血病P388、人胃癌SGC-7901有一定的抑制活性。     

水飞蓟宾衍生物的设计合成及抗肿瘤活性研究

目的 设计合成一系列新型水飞蓟宾衍生物,进行生物活性测试及分子对接研究。方法 以天然产物水飞蓟宾为先导化合物,对其C-23位羟基进行结构修饰,设计合成新型水飞蓟宾衍生物;采用MTT法,用人肺癌细胞(A549)和乳腺癌细胞(MCF-7)进行初步体外抗肿瘤筛选;利用计算机辅助药物设计方法分析所合成化合物关键基团与靶蛋白的作用方式。结果 合成了12个未见文献报道的水飞蓟宾衍生物,结构均经¹H-NMR、¹³C-NMR及MS谱确证。活性测试结果表明,化合物Ⅰ₃、Ⅰ₅对肿瘤细胞的抑制活性与阳性对照药alpelisib相当。结论 经过结构修饰后的水飞蓟宾衍生物具有一定的抗肿瘤作用,值得进一步研究。     

鬼臼类衍生物的合成及抗肿瘤活性

在三氟乙酸催化下，由4′－去甲基－表鬼臼毒素10和5－烷基－4－氨基－3－巯基－1，2，4－三唑9（a-g）合成了7个目标化合物11（a-g），并对它们进行了ＨＬ－６０、Ｋ５６２细胞株体外活性试验，结果表明：１１（a-g）对Ｋ５６２细胞株显示出较强的活性。     

4-酰胺基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

4′-去甲表鬼臼毒素与叠氮酸在三氟化硼乙醚存在下缩合,并经还原得4-氨基-4-脱氧-4′-去甲表鬼臼毒素。该中间体与酸或酸酐反应得相应酰胺化合物24个。经体外筛选,多数化合物抑制L₁₂₁₀和KB细胞活性相当或超过依托泊甙。与相应的醚、酯、胺等类型相比,这一类化合物活性最强。     

鬼臼毒素抗肿瘤作用研究进展

近年对鬼臼毒素的有效成分及其衍生物进行了较深入的抗肿瘤作用研究。本文就其抗肿瘤的作用机理、，体内过程和抗免疫作用作一综述，为进一步开发抗肿瘤药物提供依据。     

鬼臼毒素衍生物的构效关系分析及相关新药的研发思路

鬼臼毒素具有良好的抗肿瘤活性,但其水溶性差且毒副作用明显,使其临床应用受到限制。为降低毒性、提高疗效,国内外研究人员对鬼臼毒素进行了结构修饰,合成了大量具有抗肿瘤活性的鬼臼毒素类衍生物。综述近年来鬼臼毒素类化合物的结构修饰、药理活性及构效关系的研究进展。     

鬼臼酮及其肟衍生物的合成与抗肿瘤活性

为进一步考察鬼臼毒素C_4位取代基侧链的空间取向对分子活性的影响,设计并合成了标题化合物。药理试验提示将其C_4位结构转变为重键官能团,导致抗肿瘤活性减弱。     

4-酰胺基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

4′-去甲表鬼臼毒素与叠氮酸在三氟化硼乙醚存在下缩合,并经还原得4-氨基-4-脱氧-4′-去甲表鬼臼毒素。该中间体与酸或酸酐反应得相应酰胺化合物24个。经体外筛选,多数化合物抑制L_(1210)和KB细胞活性相当或超过依托泊甙。与相应的醚、酯、胺等类型相比,这一类化合物活性最强。     

Synthesis and biological evaluation of novel podophyllotoxin analogs as antitumor agents

A series of 4β N-indole-substituted podophyllotoxin derivatives were synthesized. Nine target compounds were evaluated against human cancer cell lines (HeLa, K562, and K562/A02) using MTT assay including three imine derivatives 8, 9, and 10in vitro. The result showed that the three compounds had higher antitumor activity than their reduced forms. Among them, compounds 8, 9, 11, and 16 were superior to the positive control VP-16.     

Synthesis and antitumor activity of novel podophyllotoxin derivatives against multidrug-resistant cancer cells

Seven novel 4β-N-substituted podophyllotoxin derivatives with indole rings were prepared and evaluated for cytotoxicity against human cancer cell lines HeLa, KB, KBV, K562, and K562/AO2. Most of them demonstrated improved antitumor activity and weak multidrug resistance compared to the drugs currently available.     

Synthesis and evaluation of novel amonafide–polyamine conjugates as anticancer agents

With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three‐position of amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing, and the protein expression of cyclic D1 and MMP9. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side‐effects compared to that of amonafide.     

Synthesis and evaluation of some novel benzothiazole derivatives as potential anticancer and antimicrobial agents

Intensive efforts are underway worldwide to develop anticancer and antimicrobial agents. Therefore, a novel series of pyrido[2,1-b]benzo [d]thiazole and 2-(benzo [d] thiazol-2-ylamino)pyrimidine derivatives was synthesized. The synthesized compounds were evaluated for their anticancer activity. Among the tested compounds, compounds 3a, 3b, and 7 exhibited more cytotoxic action than the control drug doxorubicin (CAS 23214-92-8; IC50: 52 microg/ml). Compound 7 was the most potent cytotoxic, with an IC50 of 42.55 pg/ ml, while compounds 3a and 3b induced high cytotoxic action with IC50 values of 50.15 pg/ml and 50.45 pg/ml, respectively. Moreover, the synthesized compounds were screened for their antibacterial and antifungal activities. Compound 6 exhibited moderate antifungal activity against C. albicans with a minimum inhibitory concentration of 125 pg/ml.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Design,synthesis, biological evaluation,and 3D‐QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents

The advancement of cancer‐fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high‐throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4‐oxadiazole was brought in to the C‐4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin‐derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF‐7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC₅₀ = 2.54 ± 0.82 μm against MCF‐7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF‐7 in a way depending on the dosage. The time‐ and dose‐dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D‐QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.     

Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives

Ten novel oleanolic acid (OA) derivatives were synthesized through modifications at positions of A ring and C-28. Inhibitory activities of the oleanolic acid derivatives against SGC7901 and A549 cell lines were evaluated and confirmed by the tetrazolium bromidesalt (MTT) assay. The lab results revealed that all these compounds displayed some antitumor activity against SGC-7901 and A-549 cell lines. Among them, II₄ and II₅ exhibited excellent antitumor activities against SGC7901 cells and A549 cells, compared with gefitinib. Molecular docking studies have shown that compounds II₄ and II₅ produce potent antitumor activities by interacting with C-kit receptor through hydrogen bonds and hydrophobic bonds.     

新型鬼臼毒素类似物的合成、构型确定及细胞毒作用研究

目的 对鬼臼毒素的A环及D环进行结构改造,以期获得合成潜在候选药物的关键中间体。 方法 以去甲表鬼臼毒素 (DMEP) 为起始原料,经醚裂解、甲基化、水解、PDC氧化、NaBH4还原、Swern氧化等反应制备得到了6个鬼臼毒素开环衍生物。结果与结论 目标产物结构经1H-NMR、HR-MS确证,并结合构象分析和1H-NMR偶合常数的测定提出了确定D环开环类似物中C8&;#61602;位构型的方法。