C-3芳苄叉基取代氧氟沙星不饱和酮衍生物的合成及抗肿瘤活性

目的 进一步优化氟喹诺酮C-3羧基等排体以期提高其抗肿瘤活性.方法 基于片段和药效团骨架迁越药物分子设计策略,用C-3羧基的等排体-芳苄叉基与氟喹诺酮骨架的4-羰基构建新的α,β-不饱和酮药效团,设计合成了C-3芳苄叉基取代氧氟沙星不饱和酮目标化合物(3a～3l).用元素分析和光谱数据确证化合物的结构,MTr法评价体外...     

C-3芳节叉基噻二唑并均三唑酮氧氟沙星衍生物的合成及抗肿瘤活性

目的发现氟喹诺酮由抗菌活性向抗肿瘤活性转化的有效结构修饰策略。方法基于药效团和骨架迁越药物设计原理,用均三唑杂环和α,β-不饱和酮分别作为C-3羧基的等排体和稠合修饰基,设计合成了C-3噻二唑并均三唑不饱和酮目标化合物(6a^61)。用元素分析和光谱数据确证化合物的结构,四甲基偶氮唑盐微量酶反应比色法(MTT)方法评价了目标化合物体外对SMMC-7721、Capan-1和HL603种癌细胞株的抗增值活性。结果合成了12个新结构的C-稠杂环不饱和酮化合物,体外抗肿瘤活性显著强于母体化合物1,其中含氟苯基和邻甲氧苯基化合物的活性与对照抗肿瘤药多柔比星相当。结论噻二唑并均三唑不饱和酮骨架替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。     

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目的 为发现抗菌氟喹诺酮向抗肿瘤活性转化的有效修饰策略。方法 以均三唑为氧氟沙星C-3羧基的等排体、通过缩环合反应设计了C-3噻二唑并均三唑稠杂环目标化合物(5a~5l,6a~6l)。用元素分析和光谱数据确证化合物的结构,用MTT方法评价了目标化合物对体外培养的SMMC-7721、Capan-1和HL60 3种癌细胞株的抗增值活性。结果 合成了12个新型结构的C-3稠杂环目标化合物,体外抗肿瘤活性强于母体1和相应中间体硫醚酮5的活性,但弱于硫醚酮缩氨基硫脲化合物6的活性。结论 C-3稠杂环等排体的结构修饰值得进一步研究。     

氟喹诺酮C-3均三唑酰腙及均三唑腙衍生物的合成和抗肿瘤活性研究(Ⅴ)

目的发现由抗菌氟喹诺酮转化为抗肿瘤氟喹诺酮的有效结构修饰方法。方法均三唑杂环作为氧氟沙星(1)C-3羧基的等排体,功能基硫乙酰腙类及腙类为其杂环排体的修饰基团,设计合成了氟喹诺酮C-3均三唑硫乙酰腙类及C-3均三唑腙类目标化合物。用四唑盐(MTT)方法评价了目标化合物对体外培养肿瘤细胞的生长抑制活性。结果合成了14个目标化合物,体外均显示潜在的抗肿瘤活性,有意义的是腙类目标化合物的活性强于酰腙类化合物活性。结论均三唑腙结构作为C-3羧基的等排体有利于提高其抗肿瘤活性。     

抗肿瘤氟喹诺酮C-3(稠)杂环化合物双NFDE6二唑甲硫醚及其碘甲烷盐衍生物的合成(Ⅰ)

目的 寻找由抗菌氟喹诺酮向抗肿瘤氟喹诺酮转化的有效结构修饰途径。方法 以抗菌氟喹诺酮药物氧氟沙星1为原料,其相应的酰肼2与二硫化碳缩环合得C-3NFDE6二唑硫醇3中间体,然后分别与5-取代苯基-2-氯甲基-1,3,4-NFDE6二唑4a~4g缩合得含氟喹诺酮骨架的双NFDE6二唑甲硫醚5a~5g,接着用碘甲烷进行季铵化反应得相应的季铵盐6a~6g。用MTT方法评价了目标化合物5a~5g和6a~6g体外对肿瘤细胞的生长抑制活性。结果 合成了14个新的目标化合物,体外均显示潜在的抗癌活性（IC₅₀＜25 μmol·L）,其中季铵盐6a~6g的活性高于相应游离碱5a~5g的活性。结论 基于抗菌氟喹诺酮C-3杂环的抗肿瘤氟喹诺酮的设计值得进一步研究。     

4-氨基-2-三氟甲基喹唑啉衍生物的合成及其体外抗肿瘤活性研究

目的 基于喹唑啉为母核设计发现新型抗肿瘤活性化合物。方法 以邻氨基苯甲酰胺和三氟乙酸酐为起始原料采用缩合、环化、氯代和偶联反应等合成了一系列4-氨基-2-三氟甲基喹唑啉衍生物(5a~5u)。采用四甲基偶氮唑盐(MTT)法评价所得目标化合物对人肺癌细胞A549、人宫颈癌细胞Hela、人白血病细胞K562、人前列腺癌细胞PC-3、人前列腺癌细胞LNCaP这5种肿瘤细胞的体外增殖抑制活性。结果 化合物5c在5 μmol·L^-1时对PC-3肿瘤细胞的抑制率为49.3%,化合物6a对LNCaP和K562、以及6b对PC-3的抑制率超过了50.0%。结论 本实验设计合成的4-氨基-2-三氟甲基喹唑啉类化合物多数具有一定的抗肿瘤活性,特别是4-氨基的N-甲基化产物6a、6b的体外抗肿瘤活性较原型化合物(5n与5u)显著增强,为该类化合物的进一步研究提供参考。     

槲皮素-3-O-酰基酯的合成及抗肿瘤活性研究

目的 合成槲皮素-3-O-酰基酯,探索抗肿瘤活性。方法 以芦丁为原料,经苄基化保护、酸水解、酯化反应,再经钯/碳(Pd/C)催化加氢脱苄基得到12种槲皮素-3-O-酰基酯,使用红外(IR)、氢谱(¹H-NMR)、碳谱(¹³C-NMR)、液质联用(ESI-MS)测定结构,采用邻二氮菲法和1,1-二苯-2-苦基肼(DPPH)法考察了12种目标化合物的抗氧化活性,采用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)法测定抗肿瘤活性。结果 光谱确定了目标化合物的结构,抗氧化性实验显示,大部分目标化合物的清除率(SC₅₀)小于槲皮素或与槲皮素相当,提示3-OH不是槲皮素抗氧化活性的必需基团,目标化合物对人食管癌细胞EC109、人食管鳞癌细胞EC9706、人胃癌细胞MGC-803、人前列腺癌细胞PC-3四株肿瘤细胞的体外增殖抑制作用增强。结论 合成了12个目标化合物,与母体槲皮素比较,对肿瘤细胞的增殖抑制作用显著增强。     

氟喹诺酮C-3酰腙的合成与抗菌活性

 目的 评价氟喹诺酮C-3位羧基被酰腙替代对其抗菌活性影响,为进一步扩大结构修饰提供新的途径。方法 第三代氟喹诺酮类药物氧氟沙星及环丙沙星为起始原料,经肼解成其相应的酰肼,然后分别与芳香醛进行缩合得系列C-3酰腙目标化合物。用琼脂稀释法研究了目标化合物体外对标准菌株金黄色葡萄球菌(S. aureus ATCC29213)、大肠埃希氏菌(E. coli ATCC25922)、铜绿假单孢菌(P. aeruginosa ATCC2785)的生长抑制活性。结果 合成了12个新的目标酰腙化合物,体外活性结果表明,氧氟沙星类酰腙化合物表现出较弱的体外抗菌活性(其MIC＞128 μg·mL^-1),而多数环丙沙星类酰腙化合物却表现出较强的体外抗菌活性(其MIC＞8 μg·mL^-1),尤其是香草醛环丙酰腙(5d)对S. aureus及E. coli的MIC≥0.5 μg·mL^-1,对P. aeruginosa的MIC≥1.0 μg·mL^-1,其抗菌活性与对照环丙沙星相当(MIC≥0.5 μg·mL^-1),而优于氧氟沙星(MIC≥2.0 μg·mL^-1)。结论 抗菌药氟喹诺酮C-3位羧基被其他取代基替代值得进一步研究。
     

(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物作为CDK9抑制剂的设计合成及抗HIV-1活性研究

目的 设计合成(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物,并对其抗HIV-1的活性进行研究。方法 4-氨基苯甲酸乙酯为起始原料,通过5步反应合成了目标化合物,采用荧光素酶(luciferase)报告基因检测了合成化合物对于HIV-1转录抑制活性。结果 目标化合物对于HIV-1的转录具有一定的抑制活性。其中化合物7p活性最优,在2 μmol·L^-1浓度下HIV-1转录抑制率为(73±0.05)%,在20 μmol·L^-1浓度下HIV-1转录活性为(90±0.01)%。进一步研究表明,化合物7p以浓度依赖性在NH1和NH2细胞中抑制HIV-1的转录活性以及下调RNA聚合酶Ⅱ CTD二号位丝氨酸磷酸化。最后,分子对接表明化合物7p与CDK9有很强的结合作用。结论 该系列化合物具有较好的抗HIV-1的活性,具有进一步研究的意义。     

替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物的简便合成

目的 研究替尼类药物的关键中间体N-芳基喹唑啉-4-胺化合物的新合成方法,优化反应条件,确定反应底物适用性,推测反应可能机理。方法 以取代邻氨基苯甲腈(1a～1e)和芳胺(2a～2e)为原料,甲酸为反应底物和溶剂,Cu(OTf)₂为催化剂,发生多组分串联反应一锅合成N-芳基喹唑啉-4-胺化合物(3a～3g),考察催化剂及用量、溶剂、反应物用量、反应温度和反应时间对反应的影响。结果 在Cu(OTf)₂的催化下,取代邻氨基苯甲腈、芳胺和甲酸能顺利发生串联的加成/缩合/环化反应,在取代邻氨基苯甲腈5 mmol,芳胺6 mmol,Cu(OTf)₂ 0.5 mmol,甲酸20 mL,110 ℃反应12 h的条件下,以80%～95%的收率得到7个N-芳基喹唑啉-4-胺化合物,目标产物结构经¹H-NMR和¹³C-NMR确证。结论 该方法为合成替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物提供了一种高效简便的绿色工艺,反应条件温和,产物收率高,操作安全简便,对环境友好。     

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??OBJECTIVE To explore an efficient strategy for converting the antibacterial activity of fluoroquinolones to antitumor activity. METHODS An amide group as an isostere modified by rhodanine unsaturated ketone moiety corresponding to the C-3 carboxylic acid group resulted in 12 new title C-3 (5-arylidene-2-thioxo-1, 3-thiozolidin-2,4-dione-3-yl) amides (6a-6l) from ofloxacin 1. Their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested cell lines was evaluated by MTT assay. RESULTS Twelve new title compounds were synthesized from ofloxacin and exhibited significantly higher potency than the parent compound ofloxacin. CONCLUSION Using a rhodanine unsaturated ketone hybrided amide group as the C-3 bioisostere is favorable to improve antitumor activity.     

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??OBJECTIVE To synthesize 5-substituted indole-3-deoxypodophyllotoxin derivatives and study their antitumor activity. METHODS The target compounds were synthesized through a series of reactions and their anti-tumor activity in vitro were evaluated against Hela, K562 and K562/A02 cell lines by MTT as assay. RESULTS Ten target compounds were synthesized and confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. All the target compounds had different degrees of cytotoxic activity in vitro. Most of the compounds had significant anti-MDR activity in vitro. CONCLUSION 5-Substituted indole-3-deoxypodophyllotoxin derivatives have good antitumor activity and worth of further study.     

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??OBJECTIVE To design and synthesize a series of oleanolic acid analogs posessing anti-tumor activity based on survivin target. METHODS Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through using the natural product, oleanolic acid, as a lead compound, the active groups were introduced onto its A-ring, and the carboxyl group at the C-28 position was modified using amidation. SGC-7901 and A549 cells were used to screen the antitumor activity in vitro through the standard MTT method. RESULTS Ten new oleanolic acid derivatives were designed and synthesized,and their structures were confirmed by MS and NMR. The compounds ??₅ and ??₅ exhibited more potent cytotoxicity than the positive control drugs. CONCLUSION The novel oleanolic acid analogues have better antitumor activity than the parent compound, which are worthy of further study.     

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??OBJECTIVE To design and synthesize 4-phenoxy-6,7-disubstituted quinolines possessing thiazolinone scaffolds and investigate their in vitro antitumor activities. METHODS Taking the c-Met kinase inhibitor cabozantinib as lead compound and based on the obtained SARs, combination principles and local modification, target compounds were prepared by nucleophilic substitution, nitration, reduction and condensation, etc. The c-Met inhibition and in vitro antitumor activities were evaluated by HTRF and MTT methods, respectively. The cytotoxicity against cancer cells was evaluated by real-time dynamic living cell imaging. RESULTS Seventeen novel compounds were obtained, and their structures were confirmed by ¹H-NMR, ¹³C-NMR and HRMS. In vitro bioassay indicated that all the compounds showed inhibitory activities against A549, HepG2 and MDA-MB-231 cell lines as well as c-Met kinase. Compound m2 exhibited potent cytotoxicity with IC₅₀ values of 2.45, 4.01, and 1.05 ??mol??L^-1, respectively. CONCLUSION The series of compounds show preferable antitumor activities, which are worthy of further study.     

6-�л�-3-����-7H-����[3,2-b]-1,2,4-���-7-ͪ�໯����ĺϳɼ�������������ø���ƻ���

??OBJECTIVE To explore the synthesis and acetylcholinesterase inhibitory activity of 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives. METHODS Benzaldehyde and acetylglycine were used as raw materials and underwent Erlenmeyer-Pl??chl reaction, condensation reaction, hydrolysis reaction, condensation reaction to obtain 6-benzyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-ones derivatives. The derivatives reacted with substituted ??-phenacyl chlorides to generate 6-benzyl-3-(hydroxylaryl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones derivatives. Then, Williamson reaction was used to yield 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones as target compounds. RESULTS Nine 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were prepared as target compounds. All target compounds exhibited inhibitory activities against human AChE in vitro, five of which had inhibitory rates above 50% at 10 ??mol??L^-1. CONCLUSION Based on the screening results of AChE inhibitory activity in vitro and docking studies, there are some interactions between 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives and the anionic binding site and PAS zones of AChE, and the target compounds have exhibited AChE inhibitory activities.     

巨噬细胞膜仿生白蛋白纳米体系的构建及其胶质瘤靶向递药性能评价

目的 构建包载WEE1激酶抑制剂adavosertib的巨噬细胞膜仿生白蛋白纳米粒(MM-BSA/Ada),体外评估其作为胶质瘤靶向递药体系的可行性。方法 制备MM-BSA/Ada并筛选最佳膜-核比和最佳药-载比,检测其载体安全性和对C6胶质瘤细胞抗增殖活性,考察其体外细胞摄取、跨血脑屏障转运和跨膜后摄取的能力。结果 MM-BSA/Ada具有良好的稳定性,CCK-8结果初步显示,未载药纳米粒在体外细胞实验中对脑血管内皮细胞呈低毒性;与未包膜纳米粒和游离药物相比,MM-BSA/Ada给药后的体外抗胶质瘤细胞增殖活性(P＜0.001)、胶质瘤细胞摄取量(P＜0.001)、体外血脑屏障透过量(P＜0.01)及跨膜后摄取量(P＜0.001)均显著提高。结论 MM-BSA/Ada有较好的胶质瘤靶向递药性能,有望为胶质瘤提供新的放射增敏策略。