滇姜花抗肿瘤活性二萜及其光敏氧化反应的研究

从滇姜花（ＨｅｄｙｃｈｉｕｍｙｕｎｎａｎｅｎｓｅＧａｇｎｅｐ．）根茎中分离到两个具抗肿瘤活性的二萜成分滇姜花素Ｃ及滇姜花素Ａ,前者为新化合物,其结构经波谱及化学方法鉴定。此新化合物亦可从滇姜花素Ａ的光敏氧化反应产物中分离得到。     

Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

A key series of vinblastine analogs 7–13, which contain modifications to the C20′ ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20′ side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R = F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R = F (equipotent with H) > N₃, CN (10-fold) > Me (50-fold) > Et (100-fold) > OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20′/C15′-fused six-membered ring.     

Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design,synthesis, biological investigation and docking studies

In an attempt to develop potent anti-tubulin agents against most dreadful disease cancer, a library of 28 novel triazole tethered isatin-coumarin hybrids were synthesized by click chemistry approach. Synthesized hybrids were characterized and evaluated against a panel of human cancer cell lines viz. THP-1, COLO-205, HCT-116 and PC-3. Biological assay unveiled that, compounds A-1 to A-6, B-1 to B-4 and C-1 to C-3 displayed significant inhibitory potential against THP-1, COLO-205 and HCT-116 cell lines which were more sensitive towards the designed hybrids. PC-3 among these cell lines was found to be almost resistant. Established SAR revealed marked dependence of the cytotoxic activity on the type of substituent on isatin and the length of carbon-bridge connecting isatin moiety with triazole ring. Unsubstituted isatin and two carbon-bridge were found to be crucial for cytotoxicity. Three most potent hybrids (A-1, A-2 and B-1) were further tested for tubulin polymerization inhibition. Among these three compounds, A-1 found to be endowed with most prominent tubulin polymerization inhibition potential with IC₅₀ value of 1.06 µM which was further confirmed by using confocal microscopy. Possible binding interactions between the most potent hybrid molecule A-1 and tubulin were also divulged by molecular modeling studies.     

Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI₅₀ values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI₅₀ of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.     

Synthesis of 2-morpholinetetraphenylporphyrins and their photodynamic activities

A series of 2-morpholinetetraphenylporphyrins functionalized with various substituents (Cl, Me, MeO group) at 4-phenyl position were prepared via nucleophilic substitution of 2-nitroporphyrin copper derivatives with morpholine by refluxing under a nitrogen atmosphere and then demetalization. Their basic photophysical properties, intracellular localization, cytotoxicities in vitro and in vivo were also investigated. All synthesized photosensitizers exhibited longer maxima absorption wavelengths than Hematoporphyrin monomethyl ether (HMME). They showed low dark cytotoxicity compared with that of HMME and were more phototoxic than HMME against Eca-109 cells in vitro. M3 also exhibited better photodynamic antitumor efficacy on BALB/c nude mice at a lower concentration. Therefore, M3 is a promising antitumor photosensitizer in photodynamic therapy application.     

Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity

The paper describes synthesis of several novel thiosemicarbazone derivatives. Furthermore, crystal and molecular structure of 4-diethylamino-salicylaldehyde 4-phenylthiosemicarbazone revealed planarity of conjugated aromatic system, which suggested the possibility of DNA binding by intercalation, especially for here studied naphthalene derivatives. However, here presented DNA binding studies excluded this mode of action. Physicochemical and structural properties of novel derivatives were compared with previously studied analogues, taken as reference compounds, revealing distinctive differences. In addition, novel thiosemicarbazone derivatives (1, 2 and 5–8) clearly display stronger antiproliferative activity on five tumor cell lines than the reference compounds 3 and 4, which supports their further investigation as potential antitumor agents.     

红色诺卡氏菌的生物活性

为了考察红色诺卡氏菌菌体(NC)的生物活性, 通过一定浓度的NC对小鼠灌胃给药, 检测其毒性及对免疫器官、巨噬细胞(MΦ)吞噬功能的影响和对肉瘤S180抑制作用。结果表明小鼠口服NC, LD50>10 g/kg; NC明显增加小鼠胸腺脾脏重量、提升白细胞数量和提高小鼠MΦ的吞噬活性; 对小鼠腹腔MΦ具有明显的激活作用, 激活了的MΦ能增强抑杀白色念珠菌作用, 正常的小鼠MΦ也有一定的杀菌作用, 两者差异显著; 对小鼠S180腹水型转实体瘤具有明显的抑制作用。由此得出的结论是, NC毒性低, 能显著增强机体     

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C₆H₅Me or p-Pr ⁱ C₆H₄Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC₅₀ ≤ 20 μM), while the mononuclear derivatives were not (IC₅₀ ≥ 100 μM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 μM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium–DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 μM), LD₅₀ of the mononuclear derivatives was between 5 and 10 J/cm², while for the tetranuclear derivatives LD₅₀ was approximately 2.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes and less than 0.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes. Examination of cells under a fluorescence microscope revealed the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes as cytoplasmic aggregates, whereas the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.     

仿刺参多糖抗肿瘤及对荷瘤小鼠免疫调节作用

目的 观察仿刺参多糖(AJPS)抗肿瘤及免疫调节作用.方法 采用MTT法检测AJPS对人肝癌HepG-2细胞抑制率;以Hca-F肝癌小鼠为模型,采用MTT法、放免法测定荷瘤小鼠细胞免疫指标.结果 AJPS抑制HepG-2细胞生长,抑制小鼠移植瘤生长;增强脾淋巴细胞和巨噬细胞活性,促进TNF-α和IL-2的产生.结论 AJPS具有对HepG-2细胞的直接杀伤作用;AJPS对荷瘤小鼠有免疫调节活性,在肿瘤的免疫治疗中发挥作用.     

乳酸杆菌发酵液RNA的抗肿瘤及对巨噬细胞功能的调节作用

目的研究乳酸杆菌DM9811发酵滤液中存在的100200 bp长的RNA片段（Ls-RNA）的免疫调节与抗肿瘤作用。方法采用中性红吞噬试验检测巨噬细胞吞噬功能,用L929细胞检测TNF,用免疫保护试验检测体内抗肿瘤作用。结果Ls-RNA可增强脾巨噬细胞的吞噬活性,对小鼠肝癌Hca-F的生长有抑制作用,延长小鼠的存活时间,但对TG诱导的腹腔巨噬细胞产生TNF无明显调节作用。结论Ls-RNA有一定免疫调节和抗肿瘤作用。