卟啉-肽核酸骨架分子的合成

在癌症治疗中,卟啉化合物被用作光动力疗法(PDT)的光敏试剂.当卟啉受到可见光的激发时,氯高铁原卟啉(hemin)的衍生物,如血卟啉(HPD,hematoporphyrin)的衍生物能够只在肿瘤组织中积累,并能通过单线态氧产生不可逆的损伤[1].     

meso-取代吡啶基卟啉的合成及结构表征

在癌症治疗中,卟啉化合物被用作光动力疗法(PDT)的光敏试剂.人们已经致力于制备新型卟啉化合物以用于癌症的光疗法[1,2]. 人工合成的含有吡啶盐、磺酸盐或羧酸盐等取代基的水溶性卟啉化合物能够在肿瘤组织上集聚[3].在寻找更有效的光敏剂的过程中,经过修饰的水溶性卟啉及其金属衍生物,由于它们能集聚在肿瘤组织并在光照下表现出较好的光敏活性,已引起了广泛关注.     

新型开环聚合催化剂—四苯基卟啉铝化物

四苯基卟啉氯化铝(TPPAICI)、四苯基卟啉烷氧基铝(TPPAIOR)等卟啉铝化物,能引发环氧化合物、内酯等话性聚合并进行嵌段共聚合,还能使酸酐、二氧化碳聚合。此类催化剂进行的活性聚合不被醇终止,相反,通过醇与活性链的快速交换反应,醇起到与催化剂相当的作用,从而能有效地调节聚合物的分子量。四苯基卟啉烷基铝(TPPAIR)在光照下可引发甲基丙烯酸甲酯等烯类单体进行活性聚合。     

不对称酰胺基卟啉及其锌配合物的合成,表征及光谱研究

以CH2Cl2为溶剂,通过5-(4-氨基)苯基-10,15,20-三苯基卟啉(MATPP)与异烟酸直接反应得到一种不对称酰胺基卟啉配体(H2P),并合成了其锌配合物(ZnP),利用紫外-可见光谱、红外光谱、核磁共振氢谱、元素分析等测试方法对化合物的结构加以确认.同时,结合光谱法初步研究了卟啉的自聚合性质.研究表明,紫外-可见光谱显示了卟啉的J-聚合特征,荧光量子产率由于自聚合而降低.     

用于光动力治疗的四苯基卟啉衍生物研究进展

四苯基卟啉(TPP)衍生物的重要用途之一是用于光动力治疗(PDT)来破坏肿瘤组织.本文综述了近年来可用于光动力治疗的四苯基卟啉(TPP)衍生物的合成.通过对TPP衍生物进行官能团修饰,可以改善其物理、化学及生物性质,从而合成出可能用于PDT的卟啉衍生物.     

四[对-(羧基甲氧基)苯基]卟啉金属配合物(M=Zn,Cu,Ni)的π-π配合及其二丁基锡(Ⅳ)酯衍生物的抗癌活性

自 1 92 4年 Policard发现血卟啉在癌组织内聚集以来 ,人们对利用卟啉的荧光性质检测及治疗癌症进行了广泛的研究 [1,2 ] .卟啉及金属卟啉的自聚合及与配体的 π- π配合反应对理解卟啉的生物功能具有重要意义[3～ 6] .有机锡 ( )类化合物自被发现有抗癌活性以来一直受到极大的关注 [7～ 9] .Mirisola等 [9]研究了四 (对 -羧基苯基 )卟啉有机锡 ( )酯化合物的体内抗癌活性 .我们合成了四 [对 - (羧基甲氧基 )苯基 ]卟啉的 Zn2 + ,Cu2 + ,Ni2 + 配合物及其二丁基锡 ( )酯衍生物 ,测定了它们的体外抗肿瘤活性 ,并研究了四 [对 - (羧基甲…     

锰卟啉功能化多元离子液体体系中苯乙烯及其衍生物环氧化反应

通过在中性锰卟啉分子中引入季铵阳离子和PF6-阴离子,制备了离子型锰卟啉化合物[MnTTMAPP][PF6]5,将其与[bmim]BF4及[bzmim]BF4混合构成锰卟啉功能化的多元离子液体复合体系(MnPy-MIL).实验发现,该体系可以高活性高选择性地催化苯乙烯及其衍生物的环氧化反应.与传统中性锰卟啉催化体系相比,离子型锰卟啉的抗氧化降解能力提高,卟啉自身聚合受到抑制,催化反应无需有机溶剂和轴向配体的参与,同时催化剂可以循环使用.少量水的存在可以提高MnPy-MIL体系的催化性能.     

曙红与卟啉分子间和分子内的光致相互作用

合成了以半刚性链(一CH_2phCH_2—)和柔性链(—(CH_2)_4—)连接的曙红-卟啉二元化合物及其模型化合物.通过吸收光谱、荧光光谱、激发光谱及荧光寿命研究了模型化合物分子间的相互作用和二元化合物分子内的光致电子转移和能量传递.结果表明:二元化合物的模型化合物曙红乙酯和卟啉易形成基态复合物 在二元化合物分子内激发曙红时,曙红能将其单重态能量传递给卟啉,并能引发分子内的电子转移;激发卟啉时,能发生曙红向卟啉的电子转移.分析了分子构型和溶剂极性对2种过程的影响.     

烷基钴卟啉[(TPP)CoR]的电化学合成和现场伏安/现场光谱电化学研究

本文报道甲基、乙基、丙基和丁基钴卟啉化合物的电化学合成和现场伏安、现场光谱电化学研究,烷基化反应的速度被确定.这些烷钴卟啉还原反应生成烷基饱和的四苯基chlorin钴化合物.     

烷基钴叶啉[(TPP)CoR]的电化学合成和现场伏安/现场光谱电化学研究

本文报道甲基、乙基、丙基和丁基钴卟啉化合物的电化学合成和现场伏安、现场光谱电化学研究.烷基化反应的速度被确定.这些烷基钴卟啉还原反应生成烷基饱和的四苯基chlorin钴化合物.     

Mitochondrion-anchoring AIEgen with Large Stokes Shift for Imaging-guided Photodynamic Therapy

Photosensitizers that can target and accumulate in mitochondria are expected to achieve good therapeutic effects in photodynamic therapy,as mitochondria are the energy generation factory in cells.Herein,we designed and synthesized a novel mitochondrion-targeting photosensitizer TPC-Py with aggregation-induced emission characteristics for image-guided photodynamic therapy.TPC-Py possessed an efficient production of 1O2,with a quantum yield of 11.65%,upon mild white light irradiation(6 mW/cm²).TPC-Py exhibited good biocompatibility under dark condition,but showed remarkable cytotoxicity towards human cervical carcinoma(HeLa)cells with a half maximal inhibitory concentration(IC50)of 3.2μmol/L when exposed to white light irradiation(14.4 J/cm²).In addition,the Stokes shift of TPC-Py was as high as 150 nm,so that it could prevent self-absorption and increase the signal-to-noise ratio of fluorescence imaging.The excellent performance of TPC-Py makes it a promising candidate in imaging-guided clinical PDT for cancer in the near future.     

Association of Ceramide Accumulation with Photodynamic Treatment-Induced Cell Death

Abstract— Ceramide, a stress-induced second messenger, has been associated with apoptosis in several malignant and non-malignant cell lines. We have shown that photodynamic treatment (PDT), using the phthalocyanine photosensitiz-er Pc 4 (HOSiPcOSi[CH₃]₂[CH₂]₃N[CH₃]₂), causes increased ceramide generation and subsequent induction of apoptosis in L5178Y-R (LY-R) mouse lymphoma cells. To test further if ceramide generation accompanies photocytotoxicity, we treated various cell lines with a PDT dose producing a 99-99.9% loss of clonogenicity. Like LY-R cells, human leukemia (U937) cells underwent rapid DNA fragmentation initiating within 1 h after PDT. Similarly, Chinese hamster ovary (CHO) cells showed rapid DNA laddering, beginning 1 h following the treatment. In contrast, mouse radiation-induced fibrosarcoma (RIF-1) cells showed no apoptosis within 24 h post-PDT, as judged by the absence of 50 kbp and oligonucleosome-size DNA fragments, as well as no annexin V binding to cells with preserved membrane integrity. Using the same doses of PDT, we observed a time-dependent ceramide accumulation in all three cell lines. While a significant increase in ceramide levels was reached within 1 and 10 min in U937 and CHO cells, respectively, elevated ceramide production was measured only after 30 min in RIF-1 cells. In addition, exogenous N-acetyl-sphingosine was able to mimic PDT-induced apoptosis in U937 and CHO cells. We suggest that ceramide accumulation is associated with PDT-induced apoptosis and photocytotox-icity.     

Highly-efficient photosensitizer based on AIEgen-decorated porphyrin for protein photocleaving

An AIEgen decorated porphyrin (TPETPyP) with ¹O₂ quantun yield as high as 0.85 in PBS was facilely prepared through a simple one-step reaction for efficient photocleavage of proteins in PDT.     

Synthesis and Activity Evaluation of Novel Prenylated Flavonoids as Antiproliferative Agents

Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3',4',7-tetramethoxy-8-prenyl-5-hydroxy flavonoid(16) was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines(HeLa, HCC1954 and SK-OV-3). The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration(IC₅₀) values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3',4',7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid(12) exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC₅₀ values of 0.91-7.08 μmol/L. 3',7-Dimethoxy-5-O-prenyl flavone(6) and 3',4',7-trimethoxy-5-O-prenyl flavone(10) showed selective antiproliferative activity against HCC1954 cells with IC₅₀ value of 0.49 and 5.32 μmol/L, respectively.     

SITES OF PHOTODYNAMICALLY INDUCED DNA REPAIR IN HUMAN CELLS

Abstract Human REH cells were incubated with the photosensitizers meso -tetra(4-sulfonatophenyl)porphyrin (TSPP=TPPS₄) or meso -tetra(3-hydroxyphenyl)porphyrin (3-THPP). The relatively hydrophilic TSPP was partly found in the cytoplasm and partly in the nuclei, whereas the lipophilic 3-THPP was found apparently in membranes and not inside the nuclei. After illumination, sites of DNA repair were labeled by means of a monoclonal antibody against proliferating cell nuclear antigen (PCNA) bound in the nuclei. The amount of bound PCNA in non-S-phase cells was proportional to the light dose. The bound PCNA was homogeneously distributed in the nuclei 0.5 h after photodynamic treatment (PDT) with TSPP. In contrast, for cells given PDT with 3-THPP, the periphery of the nuclei was selectively labeled, indicating that the initial DNA damage was localized close to the sensitizer at the nuclear membrane.     

阿糖胞苷金属卟啉衍生物的合成及光动力抗肿瘤活性

设计并合成了阿糖胞苷卟啉衍生物(AHP), 并通过金属插入反应获得了4种金属卟啉衍生物, 采用核磁共振、红外光谱、紫外-可见光谱和质谱等手段对化合物的结构进行了表征.光动力抗肿瘤活性实验结果表明, 含药浓度为25 μmol/L的ZnAHP经光照30 min后对人乳腺癌MCF-7细胞的光动力杀伤率平均达(45.86±8.20)%.     

Cellular uptake and photocytotoxicity of glycoconjugated porphyrins in HeLa cells

Thirty-two glycoconjugated porphyrins were synthesized by a modification of Lindsey method in the presence of Zn(OAc)(2).2H(2)O as a template. The Zn(2+) ion template strategy improved the yield about three-fold in the case of meta-substituted tetraphenylporphyrins. In addition, free-base porphyrins were obtained almost quantitatively by demetalation with 4 M HCl. Sixteen deacetylated glycoconjugated porphyrins were tested as candidate photodynamic therapy (PDT) drugs using HeLa cells. Most of the deacetylated glycoconjugated porphyrins showed higher cellular uptake than tetraphenylporphyrin tetrasulfonic acid (TPPS), and 5,10,15,20-tetrakis[4-(beta-D-arabinopyranosyloxy)phenyl]porphyrin (p-5d) in particular showed 18.5-fold higher uptake than TPPS. The photocytotoxicity of 5,10,15,20-tetrakis[4-(beta-D-glucopyranosyloxy)phenyl]porphyrin (p-5a), p-5d and TPPS was examined with HeLa cells, using a light dose of 16 J/cm(2). These photosensitizers had no cytotoxicity in the dark, but their photocytotoxicity increased in the order of TPPS < p-5a < p-5d. These results suggest p-5d is a good candidate for a PDT drug.     

Amino acid derivatives of pyropheophorbide-α ethers as photosensitizer: Synthesis and photodynamic activity

Ten new water-soluble amino acid conjugates of pyropheophorbide-α ethers 4a-4j were synthesized and investigated for their in vitro photodynamic antitumor activity. The results showed that all compounds exhibited higher phototoxicity and lower dark toxicity against three kinds of tumor cell lines than BPD-MA. In particular, themost phototoxic compound 4d and 4j individually showed IC₅₀ values of 41 nmol/L and 33 nmol/L against HCT116 cell, which represented 7.8- and 9.7-fold increase of antitumor potency compared to BPD-MA, respectively, suggesting that they were promising photosensitizers for PDT applications because of their strong absorption at long wavelength (λ_max>650 nm), high phototoxicity, low dark cytotoxicity and good water-solubility.     

Syntheses and Anti-cancer Activities of Derivatives of Tetrandrine and Fangchinoline

A series of derivatives of tetrandrine and fangchinoline was designed and synthesized to find more active anti-cancer compounds. Their anti-cancer activities were tested against human hcpatocellular carcinoma BEL-7402 and PLC/PRF/5 cells, human lung adenocarcinoma A549 cells as well as human leukaemia K562 cells, and the structure-activity relationship（SAR） was also studied. All the compounds except BI exhibited superior inhibitory ac- tivities against PLC/PRF/5 cells with half maximal inhibitory conccntration（ICs0） values of less than 15 μmol/L, and compounds A2, A4, B2 and B4 showed IC50 values of less than 9 pmol/L. Compounds A2, A6, B2 and B4 showed potent anti-cancer activities against all the tested cells with 1C5o values of less than 10 pmol/L. The results show that terandrine and fangchinoline derivatives are potential suppressors to human cancer.     

Visible‐Light‐Induced Annihilation of Tumor Cells with Platinum–Porphyrin Conjugates

Despite the extensive use of porphyrins in photodynamic therapy (PDT), tetraplatinated porphyrins have so far not been studied for their anticancer properties. Herein, we report the synthesis of such novel platinum–porphyrin conjugates as well as their photophysical characterization and in vitro light‐induced anticancer properties. These conjugates showed only minor cytotoxicity in the dark, but IC₅₀ values down to 19 nM upon irradiation with light at 420 nm.These values correspond to an excellent phototoxic index (PI=IC₅₀ in the dark/IC₅₀ in light), which reached 5000 in a cisplatin‐resistant cell line. After incubation with HeLa cells, nuclear Pt concentrations were 30 times higher than with cisplatin. All of these favorable characteristics imply that tetraplatinated porphyrin complexes are worthy of exploration as novel PDT anticancer agents in vivo.