熊果酸衍生物的合成及对前列腺癌PC-3细胞的抑制活性

目的:合成具有不同电负性基团的熊果酸衍生物并研究其抗癌活性。方法:合成一系列携带正电性基团或负电性基团的熊果酸衍生物,并用软件预测衍生物油水分配系数及水溶性的改善情况;采用MTT法考察熊果酸衍生物对人前列腺癌PC-3细胞的抑制活性;采用细胞周期分析及AnnexinV/PI双标记法探讨其抗癌机制。结果:熊果酸衍生物的水溶性较熊果酸有明显改善;荷负电基团的熊果酸衍生物抑癌活性远低于熊果酸,而负载正电性基团显著提高了熊果酸的体外抗癌活性,其作用机制为诱导细胞发生凋亡及细胞周期阻滞;其中熊果酸衍生物UA-3,UA-4,UA-5b的水溶性提高70倍以上,对PC-3细胞的IC50(48 h)均<10μmol.L-1,将细胞阻滞于G0/G1期并具有诱导凋亡作用(凋亡率均>50%)。结论:采用正电性基团修饰熊果酸是提高抗癌效果并改善其水溶性的有效途径之一。     

新型胰高血糖素样肽-1类似物的合成及降糖活性

目的合成具有全新肽序的新型胰高血糖素样肽-1(GLP-1)受体激动剂非洲爪蟾GLP-1并对其(XenGLP-1)进行长效化修饰。方法先通过在其C端引入PSSGAPPPS序列以增加其降糖活性,再在XenGLP-1序列上引入半胱氨酸,进一步利用MAL-PEG2 000与其进行缀合。结果合成得到PEG2 000-ZF-1和PEG2 000-ZF-2 2个缀合肽,并对缀合肽进行长效化降糖活性研究。结论 2个PEG化缀合肽具有长效的降糖活性,具有很好的药物开发前景。     

熊果酸衍生物与查耳酮缀合物的合成及抗肿瘤活性研究

目的 设计、合成喹喔啉熊果酸-查耳酮缀合物.方法 以喹喔啉熊果酸为先导化合物,将查耳酮通过酯化反应拼接到喹喔啉熊果酸得到了一系列喹喔啉熊果酸-查耳酮缀合物,并通过MTT法测试其抗癌活性.结果 合成了6个喹喔啉熊果酸-查耳酮缀合物,其结构均通过1H NMR,13C NMR和HRMS加以确认.初步的生物活性结果表明,这些缀合物对MCF-7、PC-3、GBC-823和KB细胞均有抑制活性,尤其是对MCF-7细胞的抑制活性与熊果酸相比均有提高,其中化合物5(IC50=14.2μmol·L-1),6(IC50=15.3μmol·L-1)和7(IC50=10.6μmol·L-1)对MCF-7细胞的抑制活性甚至强于临床上应用的药物他莫昔芬(IC50=15.9μmol·L-1).同时,这些缀合物对正常的乳腺上皮细胞MCF-10A没有毒性.结论 本研究为开发高效、低毒的的熊果酸衍生物提供了信息和依据.     

熊果酸与白藜芦醇缀合物的合成及其抗肿瘤活性评价

目的 设计、合成熊果酸与白藜芦醇缀合物,并对其抗肿瘤活性进行研究。方法 以熊果酸为原料,通过酯化反应合成了熊果酸-白藜芦醇缀合物,并采用MTT法评价缀合物的体外抗肿瘤活性。结果 合成了12个熊果酸-白藜芦醇缀合物,其结构经¹H-NMR和MS进行确证。初步的生物活性结果表明,目标缀合物对乳腺癌细胞MCF-7和MDA-MB-231均有抑制活性,其中缀合物13b-c和15b-c对MCF-7的抑制活性强于熊果酸、白藜芦醇及阳性药物他莫昔芬。此外,目标缀合物对正常的MCF-10A细胞没有毒性。结论 熊果酸结构中引入白藜芦醇结构单元可提高其抗肿瘤活性。     

积雪草酸C2、C3、C23、C28衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成积雪草酸C2、C3、C23、C28衍生物,并对其体外抗肿瘤活性进行研究。方法以天然产物积雪草酸为先导化合物,对C2、C3、C23位羟基及C28位羧基进行结构改造,并采用SRB法对目标化合物进行初步的体外抗肿瘤活性研究。结果设计并合成了目标化合物,利用MS及1H-NMR确证了结构;体外实验中,积雪草酸衍生物的抗肿瘤活性明显高于积雪草酸,并优于对照药吉非替尼。结论积雪草酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

木犀草素Mannich碱衍生物的合成及其抗癌活性

目的:合成木犀草素Mannich碱衍生物并考察其抗癌活性。方法:室温下木犀草素与甲醛、胺经Mannich反应得到8种Mannich碱衍生物。采用MTT法,以5氟-尿嘧啶(5-Fu)为阳性对照药,通过人宫颈癌细胞(Hela)、人胃癌细胞(SGC-7901)、人结肠癌细胞(HCT-116)、人白血病细胞(K562)、人乳腺癌细胞(MCF-7)、人前列腺癌细胞(DU-145)等6种肿瘤细胞进行体外抗癌活性评价,以正常人胚肾上皮细胞(HEK-293)为毒性对照;对化合物8h进行抗癌分子机制研究。结果:合成的8种化合物结构经1H-NMR、13C-NMR和MS确证。体外抗癌活性试验表明部分化合物显示出比木犀草素更好的抗癌活性。结论:化合物8h可能通过线粒体途径抑制SGC-7901细胞增殖,从而诱导细胞凋亡。     

新型长春西汀-维生素C缀合物的合成及抗氧化活性

目的：合成长春西汀-维生素C缀合物,并考察其生物活性。方法：以长春西汀和维生素C为起始原料,经4步反应制得目标产物长春西汀-维生素C缀合物,并采用DPPH·自由基法测定其体外抗氧化活性。结果与结论：目标产物总产率为15．8％,其结构经IR、^1HNMR、^13CNMR和MS确证。初步体外抗氧化活性研究表明,该化合物具有一定的体外抗氧化活性。     

富勒烯-苯丙氨酸多西他赛纳米脂质载体的制备及其体外抗肿瘤活性

目的 建立以光敏剂富勒烯-苯丙氨酸(C60-Phe)和多西他赛(DTX)为模型,制备纳米结构脂质载体(NLC),并考察其体外对人乳腺癌细胞MCF-7增殖抑制作用.方法 利用C60的化学活性特点合成水溶性C60-Phe衍生物;并采用高温乳化-低温固化的方法制备C60-Phe-DTX-NLC,表征其制剂学性质,同时观察NL...     

组蛋白去乙酰化酶抑制剂与加替沙星新缀合物的合成及抗肿瘤活性

目的 设计合成加替沙星-组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor, HDACi)缀合物，并探讨其抗肿瘤活性。方法 以第四代喹诺酮类药物加替沙星为原料，对其进行结构修饰，分别在其C-7哌嗪基和C-3位羧基引入辛二酰苯胺异羟肟酸(SAHA)单元，并采用HDACs试剂盒、微管蛋白试剂盒和MTT法对所合成的缀合物进行酶和抗肿瘤抑制活性测试。结果 合成了4个未见文献报道的新化合物10a~c和13，其结构均经过1H NMR、13C NMR和HRMS进行确证。初步的生物活性研究表明目标化合物能有效地抑制微管蛋白聚合和HDACs，并对5种肿瘤细胞有不同程度的抑制活性，其中SAHA类似物单元的侧链为6个亚甲基的缀合物10b和13对微管蛋白聚合和HDACs的抑制活性以及抗肿瘤活性强于其他衍生物。结论 将组蛋白去乙酰化酶抑制剂(HDACi)单元引入到加替沙星上，能提高其抗肿瘤活性。     

甘草次酸C3、C30衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成甘草次酸C3、C30衍生物,并对其体外抗肿瘤活性进行研究。方法以甘草次酸为先导化合物,对其C3位羟基、C30位羧基进行结构修饰,并采用SRB法对目标化合物进行体外抗肿瘤活性研究。结果设计合成了12个新型甘草次酸衍生物,并利用MS、1H-NMR及元素分析确证了结构;体外实验中,目标化合物对MCF-7和A549肿瘤细胞的抑制活性均明显强于甘草次酸,其中化合物GA-I1、GA-I2和GA-II1对MCF-7和A549两种细胞表现出很好的抑制活性,明显高于对照药吉非替尼。结论甘草次酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

Ursolic acid ( UA ) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and ¹H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non‐pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA . In particular, 5b demonstrated IC₅₀ values ranging from 4.09 ± 0.27 to 7.78 ± 0.43  μ m against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner.     

薯蓣皂苷元衍生物的抗肿瘤活性研究

目的研究薯蓣皂苷元衍生物在体外的抗肿瘤活性。方法采用MTT法对人恶性黑色素瘤细胞A375、人肺腺癌细胞A549、人肝癌细胞HepG-2及人慢性髓原白血病细胞株K562进行体外抗肿瘤活性试验。结果薯蓣皂苷元衍生物对4个肿瘤细胞株A375、A549、K562、HepG-2具有不同程度的抗肿瘤活性。结论绝大部分薯蓣皂苷元衍生物对4个肿瘤细胞株有较好的抗肿瘤活性,IC50值都低于30μmol.L-1。化合物22对细胞株A375的IC50=4.48μmol.L-1,化合物9、10对细胞株K562的IC50分别为2.51、2.38μmol.L-1;显示其抗肿瘤活性与对照化合物1-(3β-薯蓣皂苷元)-3-苄基咪唑溴盐相当。     

Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid‐ and Multidrug‐resistant Escherichia coli

As a part of our drug discovery program, ursolic acid was chemically transformed into six semi‐synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid‐sensitive and nalidixic acid‐resistant strains of Escherichia coli. Although ursolic acid and its all semi‐synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3‐O‐acetyl‐urs‐12‐en‐28‐isopropyl ester (UA‐4) and 3‐O‐acetyl‐urs‐12‐en‐28‐n‐butyl ester (UA‐5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid‐resistant and four and eightfold against nalidixic acid‐sensitive, respectively. The UA‐4 and UA‐5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug‐resistant clinical isolate of Escherichia coli‐KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration‐dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA‐4 and UA‐5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug‐resistant Gram‐negative infections.     

丹参新酮C环酚酯衍生物的设计合成及抗肿瘤活性研究

目的：通过对丹参新酮C环邻醌位点的结构修饰,改变其脂水分配系数(CLogP),获得系列丹参新酮酚酯衍生物,进而评价其抗肿瘤活性。方法：采用氢化还原、酰化、脱保护基等方法对丹参新酮的邻醌位点进行修饰,通过引入不同酸酐、氨基酸取代基,得到丹参新酮C环酚酯衍生物,在此基础上以前列腺癌Lncap和Du145细胞株对部分化合物进行抗肿瘤活性评价。结果：共合成了9个新的丹参新酮酚酯衍生物,其中1个化合物表现出较好的抗肿瘤活性。结论：脂水分配系数的改变对丹参新酮衍生物抗肿瘤活性影响很大,适当提高水溶性,有助于增强其抗肿瘤活性,改善成药性。     

Synthesis and anti-tumor activity of alkenyl camptothecin esters

Aim: To study the degrees of influence of changing side ester chains at position C20 of camptothecin on the anti-tumor activity of the molecules. Methods: The esterification reaction of camptothecin 1 and 9-nitrocamptothecin 2 with crotonic anhydride in pyridine gave the corresponding esters 3 and 4, respectively. The acylation of I and 2 with cinnamoyl chloride gave products 7 and 8. Epoxidation reaction of 3 and 4 with m-chloroperoxybenzoic acid in benzene solvent gave the products 5 and 6. Esters 3, 4, and 5 were tested for anti-tumor activity against 14 human cancer cell lines. Results: Both in vitro and in vivo anti-tumor activity studies for these esters were conducted and the data demonstrated positive results, that is, these esters were active against the tested tumor lines. Conclusion: Alkenyl esters 3 and 4 showed strong anti-tumor activity in vitro against 14 different cancer cell lines. Ester 3 was active against human breast carcinoma in mice and the toxicity of the agent was not observed in mice during the treatment, implying that this agent is effective for treatment with low toxicity.     

Synthesis and antitumor activity of 1,3-benzodioxole derivatives

A series of 1,3-benzodioxoles (5-19) was synthesized and evaluated for their in vitro antitumor activity against human tumor cell lines. Some derivatives exhibited tumor growth inhibition activity. In particular, 6-(4-aminobenzoyl)-1,3-benzodioxole-5-acetic acid methyl ester 8, the most active compound of the series, possesses a significant growth inhibitory activity on 52 cell lines at concentrations ranging from 10(-7) to 10(-5) M.     

Synthesis and anti-tumor activities of novel methylthio-, sulfinyl-, and sulfonyl-8H-thieno[2,3-b]pyrrolizin-8-oximino derivatives

A series of novel methylthio-, sulfinyl-, and sulfonyl-8H-thieno[2,3-b]pyrrolizin-8-oximino derivatives 7A-12P was designed and synthesized as anti-tumor agents. Their structures were confirmed by IR, (1)H-NMR, MS, and elemental analysis. The anti-tumor activities of all the target compounds were tested by the MTT method in vitro against Bel-7402 (human liver cancer) and HT-1080 (human fibro sarcoma) cell lines. Among them, compound 11N (IC(50) = 18.2 microM, 8.2 microM), was the most promising compound of all synthesized molecules, it was 2.5- and 3.3-times more active than cisplatin (IC(50) = 45.2 microM, 26.7 microM), respectively.     

Synthesis and antitumour activity of 1H,3H-thiazolo[3,4-a]benzimidazole derivatives

A series of 1H,3H-thiazolo[3,4-a]benzimidazoles were synthesized and tested for their in vitro antitumour activity against 60 human tumour cell lines. Some derivatives exhibited both tumour growth inhibition activity and cellular selectivity. In particular, compound 8c, the most active of the series, was very active towards all cell lines at concentrations ranging from 10(-7)-10(-5) M. Compound 4a, on the other hand, was highly selective against the CNS cancer cell line.     

Polyethylene Glycol-Conjugated Copolymers for Plasmid DNA Delivery

No Heading Polymeric gene delivery systems have been developed as an alternative for viral gene delivery systems to overcome the problems in the use of viral gene carriers. Polymeric carriers have many advantages as gene carriers such as low cytotoxicity, low immunogenicity, moderate transfection efficiency, no size-limit, low cost, and reproducibility. In the efforts to develop safe and efficient polymeric gene carriers, polyethylene glycol (PEG) has widely been used because of its excellent characteristics. PEG-conjugated copolymers have advantages for gene delivery: 1) The PEG-conjugated copolymers show low cytotoxicity to cells in vitro and in vivo, 2) PEG increases water-solubility of the polymer/DNA complex, 3) PEG reduces the interaction of the polymer/DNA complex with serum proteins and increases circulation time of the complex, 4) PEG can be used as a spacer between a targeting ligand and a cationic polymer. A targeting ligand at the end of a PEG chain is not disturbed by the interaction of a cationic polymer with plasmid DNA, and the PEG spacer increases the accessibility of the ligand to its receptor. In this review, PEG copolymers as gene carriers are introduced, and their characteristics are discussed.     

Novel pyrimidine and purine derivatives of L-ascorbic acid: synthesis and biological evaluation.

The novel pyrimidine derivatives 1-6 of 2,3-dibenzyl-4,5-didehydro-5, 6-dideoxy-L-ascorbic acid were synthesized by the condensation of pyrimidine bases with 5,6-diacetyl-2,3-dibenzyl-L-ascorbic acid (DDA). Both N-9 (7) and N-7 (8) regioisomers were obtained in the reaction of 6-chloropurine with 5-acetyl-6-bromo-2, 3-dibenzyl-L-ascorbic acid (ABDA), while the reaction of 6-(N-pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of all newly prepared compounds were deduced from the chemical shifts in (1)H and (13)C NMR spectra, as well as connectivities in 2D homo- and heteronuclear correlation spectra. An unambiguous proof of the structure and conformation of 7 was obtained by X-ray crystallographic analysis. Compounds 1-9 were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0), as well as antiviral activities against varicella-zoster virus (TK(+)VZV and TK(-)VZV) and cytomegalovirus (CMV). The compound 6 containing a trifluoromethyl-substituted uracil ring exhibited marked antitumor activity. The N-7-substituted purine regioisomer 8 had greater inhibitory effects on the murine L1210/0 and human CEM/0 cell lines than the N-9 isomer 7. Compound 9 with the 6-purine-substituted pyrrolo moiety had a more pronounced selective cytostatic activity against human (Molt4/C8 and CEM/0) cell lines than murine (L1210/0 and FM3A/0) and human (MiaPaCa2, MCF7, HeLa, and Hep2) tumor cell lines and normal fibroblasts (Hef522). The compound 6 exhibited the most potent antiviral activities against TK(+)VZV, TK(-)VZV, and CMV, albeit at concentrations that were only slightly lower than the cytotoxic concentrations.