Design, Synthesis and Synergistic Effects of Novel Derivatives of Solanesol

To further explore the biological activities of solanesylamine derivatives,several novel solanesylpiperazinotriamines and their amides were designed and synthesized,the chemical structures of target compounds were confirmed by IR,1H NMR,MS,and element analysis.The in vitro antitumor activities of the synthetic compounds were assessed by MTT test on L1210 and CHO cells.The preliminary results showed that at low micromolar concentrations these compounds exhibit obvious toxicity against tumor cells,and the synergistic effect on clinical antitumor agent indicated that at noncytotoxic concentrations,they also evidently enhance the curative effect of vincristine(VCR).The synergistic effects of compounds 4a,4c,and 9 were even superior to that of reference compound N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-ethylenediamine(SDB).     

Synthesis of certain 2-substituted-1H-benzimidazole derivatives as antimicrobial and cytotoxic agents

A series of 2-substituted-1H-benzimidazole derivatives were synthesized and evaluated for antimicrobial, antifungal and cytotoxic activities. The results showed that all tested compounds showed potent antimicrobial activity against some species of Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi) and fungi (Candida albicans) with minimum inhibitory concentrations (MICs) lower than 0.016 μg/mL. In contrast, all tested compounds were inactive against Staphylococcus aureus (Gram-positive bacterium). The final targets were also tested for their antitumor activity in vitro on cervical carcinoma (HeLa) cell line. Eight of the test compounds displayed more potent cytotoxic effect than doxorubicin at nanomolar concentrations. Compounds 2c and 3c exerted the strongest cytoyoxic effect with IC(50) 15 and 13 nM, respectively.     

Antitumor agents. I. DNA topoisomerase II inhibitory activity and the structural relationship of podophyllotoxin derivatives as antitumor agents.

Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210). An intact 6,7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity. The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following: 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.     

Chemometric Analysis of Urinary Volatile Organic Compounds to Monitor the Efficacy of Pitavastatin Treatments on Mammary Tumor Progression over Time

Volatile organic compounds (VOCs) in urine are potential biomarkers of breast cancer. Previously, our group has investigated breast cancer through analysis of VOCs in mouse urine and identified a panel of VOCs with the ability to monitor tumor progression. However, an unanswered question is whether VOCs can be exploited similarly to monitor the efficacy of antitumor treatments over time. Herein, subsets of tumor-bearing mice were treated with pitavastatin at high (8 mg/kg) and low (4 mg/kg) concentrations, and urine was analyzed through solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS). Previous investigations using X-ray and micro-CT analysis indicated pitavastatin administered at 8 mg/kg had a protective effect against mammary tumors, whereas 4 mg/kg treatments did not inhibit tumor-induced damage. VOCs from mice treated with pitavastatin were compared to the previously analyzed healthy controls and tumor-bearing mice using chemometric analyses, which revealed that mice treated with pitavastatin at high concentrations were significantly different than tumor-bearing untreated mice in the direction of healthy controls. Mice treated with low concentrations demonstrated significant differences relative to healthy controls and were reflective of tumor-bearing untreated mice. These results show that urinary VOCs can accurately and noninvasively predict the efficacy of pitavastatin treatments over time.     

Losartan Alleviates the Side Effects and Maintains the Anticancer Activity of Axitinib

Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant tumors. However, its severe side effects affect the quality of life and prognosis of patients. Losartan, which functions as a typical angiotensin receptor blocker, controls the average arterial pressure of patients with essential hypertension and protects against hypertension-related secondary diseases, including proteinuria and cardiovascular injury. To explore the effects of losartan on side effects caused by axitinib and its antitumor activity, several animal experiments were conducted. This study first analyzed and explored the effect of losartan on the amelioration of side effects in Wistar rats caused by axitinib. The results showed that the systolic blood pressure of Wistar rats was significantly increased by about 30 mmHg in 7 days of axitinib treatment, while the combination of losartan significantly reduced the blood pressure rise caused by axitinib. The Miles experimental model and mouse xenograft tumor model were further used to evaluate the effect of losartan on the antitumor effect of axitinib. The result clearly demonstrated that losartan has no significant influence on axitinib-related low vascular permeability and antitumor activity. In summary, our results showed that the combination of axitinib and losartan significantly reduced the side effects and maintained the antitumor effects of axitinib. This study provides information for overcoming VEGF receptor inhibitor-related side effects.     

Synthesis and tumor cytotoxicity of novel amide derivatives of β-hederin

Thirteen novel triterpenoid saponins, designed as amide derivatives of the natural cytotoxic saponin β-hederin, were synthesized by a stepwise glycosylation strategy. The in vitro cytotoxic activity of these compounds was evaluated against five different tumor cell lines. Most of the evaluated compounds showed effective inhibitory activity against at least one tumor cell line at micromolar concentrations. The preliminary structure-activity relationships (SAR) indicate that mide derivatization at C-28 resulted in highly cytotoxic derivatives on specific tumor cell lines, and also resulted in an increase in the antitumor selectivity of β-hederin.     

Structures and conformations of metabolites of antitumor cyclic hexapeptides, RA-VII and RA-X.

Metabolites of antitumor cyclic hexapeptides, RA-VII and -X which were isolated from Rubia cordifolia were studied by hepatic microsomal biotransformation in rats and in bile juice of rabbits to which these drugs were administered intravascularly. Their structures and conformations were elucidated by two-dimensional nuclear magnetic resonance techniques, temperature effect on NH protons and nuclear Overhauser effect experiments. Specific N-demethylation of Tyr-3, O-demethylation and hydroxylation at aromatic rings of Tyr-3 and -5 were observed. Compared with metabolites of RA-VII, most of RA-X was excreted unchanged in the bile juice. Relationship among their structures, conformations and antitumor activities is also discussed.     

原子类型电拓扑状态指数预测吲哚喹唑啉衍生物的抗癌性

采用原子类型电拓扑状态指数(ETSIAT)对17个吲哚喹唑啉衍生物的抗癌活性进行定量构效关系(QSAR)的研究. 经逐步回归变量筛选, 得到包含4个ETSIAT变量的最优偏最小二乘模型, 其复决定系数R2、留一法交互验证复决定系数Q2和均方根误差RMSEE分别为0.806、0.736 和0.248. 将样本随机分为训练集和预测集后, 采用相同变量组合对模型进行外部验证, 结果显示模型具有较高的外部预测能力. 模型分析结果显示, 与抗癌活性相关的4个ETSIAT描述子对应结构碎片分别为≥N=, —NH—, =O, >N—. 其中—NH—结构碎片与抗癌活性呈负相关关系, 而≥N=, >N—和=O则与抗癌活性呈正相关关系. 此外, 研究亦显示, 取代基R1上存在强的吸电子基团可显著提高化合物的抗癌活性, 且影响抗癌活性的因素可能还有R2基团的空间位阻效应. 据此设计出4个化合物的预测活性比最高活性样本分别提高7.7%、15.3%、23.1%和130%.     

Photochemically generated elemental selenium forms conjugates with serum proteins that are preferentially cytotoxic to leukemia and selected solid tumor cells

The objective of this study was to determine if and how photoproducts contribute to the antitumor effect of merocyanine-mediated PDT. A panel of barbituric, thiobarbituric and selenobarbituric acid analogues of Merocyanine 540 was photobleached, and the resulting photoproducts were characterized by absorption, fluorescence emission, mass, energy dispersive X-ray, and X-ray photoelectron spectroscopy and tested for cytotoxic activity against tumor cell lines and freshly explanted bone marrow cells. While all dyes were readily photobleached, only photoproducts of selone dyes showed cytotoxic activity. One-hour incubations with micromolar concentrations of selone-derived photoproducts were sufficient to reduce leukemia/lymphoma cells ≥10 000 fold, whereas preserving virtually all normal CD34-positive bone marrow cells. Of six multidrug-resistant tumor cell lines tested, five were as sensitive or more sensitive to photoproducts than the corresponding wild-type lines. Physicochemical characterizations of the cytotoxic activity indicated that it consisted of conjugates of subnano particles of elemental selenium and (lipo)proteins. The discovery of cytotoxic Se-protein conjugates provides a rare example of photoproducts contributing substantially to the antitumor effect of PDT and challenges the long-held view that Se in oxidation state zero is biologically inert. Agents modeled after our Se-protein conjugates may prove useful for the treatment of leukemia.     

An efficient mammalian transfer RNA target for bleomycin

The antitumor antibiotic bleomycin has long been believed to exert its therapeutic effects at the level of DNA cleavage. Recently, evidence has been presented to suggest that RNA cleavage may also be important and that one or more transfer RNAs may be involved. To define those tRNAs that may represent important loci for the action of bleomycin, we have fractionated chicken liver tRNAs and identified those isoacceptors most susceptible to oxidative cleavage by Fe(II).BLM. Two chicken liver tRNAs, tRNA3Lys and tRNAPhe, were found to be cleaved with exceptional facility by Fe(II).BLM, and both were cleaved predominantly at U66. The cleavage of tRNA3Lys was shown to be minimally affected by physiological concentrations of Mg2+. Chicken liver tRNA3Lys is identical in sequence with human tRNA3Lys. These findings support a possible role for a critical tRNA such as tRNA3Lys in the mechanism by which bleomycin mediates its antitumor activity.     

Direct zonal liquid chromatographic method for the kinetic study of actinomycin-DNA binding

The binding of an anticancer drug (actinomycin D or ACTD) to double-stranded DNA (dsDNA) was studied by means of high-performance liquid chromatography (HPLC). ACTD is an antitumor antibiotic containing one chromophore group and two pentapeptidic lactone cycles that binds dsDNA. Incubations of ACTD with DNA were performed at physiological pH. The complexed and free ligand concentrations of the mixture were quantified at 440 nm from their separation on a size-exclusion chromatographic (SEC) column using the same buffer for the elution and the sample incubation. The DNA and the ACTD-DNA complexes were eluted at the column exclusion volume while the ligand was retained on the support. An apparent binding curve was obtained by plotting the amount emerging at the exclusion column volume against that eluted at free ACTD retention volume. A dissociating effect was evidenced and the binding parameters were significantly different from those obtained at equilibrium by visible absorbance titration. The equilibrium binding parameters determined by absorption spectroscopy were used as starting data in the numerical simulations of the chromatographic process. The results showed a strong dependency of the apparent binding parameters on the reaction kinetics. Finally the comparison of the apparent binding curve obtained from the HPLC experiments and from the numerical simulations permitted an evaluation of the dissociation rate constant (kd = 0.004 s(-1)).     

Synthesis,Biological Evaluation and Molecular Docking of Novel Phenylpyrimidine Derivatives as Potential Anticancer Agents

Based on our previous researches, a novel phenylpyrimidine pharmacophore model was proposed and fifteen derivatives were synthesized and characterized by means of spectroscopy methods. The inhibitory effects of them were screened against HeLa cell line by virtue of MTT assay in vitro. The results indicate some of the phenylpyrimidine derivatives exhibit potent biological activities. Among them, compounds 6g and 6h exhibit the best activity at half maximal inhibitory concentrations of 1.5 and 2.8 μmol/L, respectively. These compounds also exhibit good activities against HepG2 cell line and MCF-7 cell line. FLT-3 kinase was screened as the most potent molecular target. Computational docking between compound 6g and FLT-3 was carried out to interpret the binding mode. The results show phenylpyrimidine derivatives have effective antitumor activities, which provides a base for further research of them as antitumor agents.     

Studies on the biological activity of tocotrienols

Tocotrienols were evaluated for activity against transplantable murine tumors inoculated i.p. into mouse, and the activities of two tocotrienols and alpha-tocopherols were compared. When the compounds were injected i.p., alpha- and gamma-tocotrienols were effective against sarcoma 180, Ehrlich carcinoma, and IMC carcinoma, and gamma-tocotrienol showed a slight life-prolonging effect in mice with Meth A fibrosarcoma, but the tocotrienols had no antitumor activity against P388 leukemia at doses of 5-40 mg/kg/d. On the other hand alpha-tocopherol had only a slight effect against sarcoma 180 and IMC carcinoma. The antitumor activity of gamma-tocotrienol was higher than that of alpha-tocotrienol. Tocotrienols showed growth inhibition of human and mouse tumor cells when the cells were exposed to these agents for 72 h in vitro, whereas tocopherol did not show any marked cytotoxic activity. Alpha- and gamma-tocotrienols had inhibitory effects on lipid peroxidation of murine microsomes by adriamycin.     

Synthesis and structure-activity relationships of fenbufen amide analogs

The previous discoveries of butyl fenbufen amide analogs with antitumor effects were further examined. The amide analogs with 1, 3, 4 and 8 carbons chains were prepared in 70-80% yield. Fenbufen had no cytotoxic effects at concentrations ranging from 10 to 100 μM. Methyl fenbufen amide had significant cytotoxic effects at a concentration of 100 μM. As the length of the alkyl amide side chain increased, the cytotoxic effects increased, and the octyl fenbufen amide had the greatest cytotoxic effect. After treatment with 30 μM octyl fenbufen amide, nearly seventy percent of the cells lost their viability. At the concentration of 10 μM, fenbufen amide analogs did not show cytotoxicity according to the MTT assay results. The NO scavenging activities of the fenbufen amide analogs were not significantly different from those of fenbufen.     

枸橼酸锗抗肿瘤作用的实验研究

观察了有机锗化合物枸橼酸锗对小鼠移植性肿瘤Ｓ１８０、Ｈ２２和Ｐ３３８的抗肿瘤作用。结果表明，枸橼酸锗０．２、０．４ｇ／ｋｇ体重灌胃给药，对小鼠Ｓ１８０的平均抑瘤率为４７．６２％和５２．３８％；对小鼠Ｈ２２的平均抑瘤率在４６．１５％和５２．２０％；对Ｐ３８８小鼠生命延长率为２４．４２％和３０．１８％，均优于对照组。     

Topoisomerases inhibitory activities and DNA binding properties of 9-methoxycamptothecin from Nothapodytes nimmoniana (J. Graham) Mabberly

We have reported previously that 9-methoxycamptothecin (MCPT) showed significant antitumor activity in vitro. Here, agarose gel electrophoresis experiments were performed to evaluate MCPT’s unwinding ability toward plasmid DNA and inhibitory activities against topoisomerases (Topo) I and II. Binding properties of MCPT to calf thymus DNA (CT-DNA) were evaluated by UV–vis, melting temperature, fluorescence, circular dichroism methodologies and molecular docking technique. Results showed that MCPT at 100 μM inhibited Topo I activity, but had no effect on Topo II. Studies on the binding properties indicated that minor groove binding was the most probable binding mode of MCPT to DNA. The abilities of MCPT to act as Topo I inhibitor and minor groove binding agent may be related to its strong antitumor activity.     

Synthesis and biological activities of lipid A analogs: modification of a glycosidically bound group with chemically stable polar acidic groups and lipophilic groups on the disaccharide backbone with tetradecanoyl or N-dodecanoylglycyl groups.

Six novel lipid A analogs were synthesized. The first two analogs, 4 and 5, have an alpha-glycosidically bound carboxymethyl or 1,3-dicarboxyisopropyl group on the disaccharide backbone with four tetradecanoyl groups. The next three analogs, 6, 7 and 8, have two or four N-dodecanoylglycyl groups on the 1-alpha-O-phosphonooxyethylated disaccharide backbone. Analog 6 bears N-dodecanoylglycyl groups on the hydroxyl functions at positions 3 and 3', and tetradecanoyl groups on the amino functions at positions 2 and 2'. Analog 7 is a 2, 3, 2' and 3'-tetrakis(N-dodecanoylglycyl) derivative, and analog 8 resembles compound 6, but the binding of the N-dodecanoylglycyl and tetradecanoyl groups at positions 2, 2' and 3, 3' are reversed. The third analog, 9, has the same acyl group configuration as compound 6, but has a 1,3-dicarboxyisopropyl group at position C-1. Compounds 4 and 5 exhibited definite antitumor activity against Meth A fibrosarcoma, indicating that the phosphate group at the C-1 position in lipid A could be replaced by the carboxylic acid without reducing the antitumor activity. In rabbits, compounds 6 and 9 exhibited potent antitumor activity, but their toxicity was extremely low. On the other hand, compounds 7 and 8 showed no antitumor activity. The levels of antitumor activity of 6 and 9 were similar to those of the natural-type lipid A. The antitumor activities of analogs with a N-dodecanoylglycyl group on the disaccharide backbone depended on the connecting sites of the acyl groups.     

Effect of Dai-Bai-Jie on the proliferation and migration of the A549 cells

Lung cancer is the most malignant tumor disease with the highest diagnosis and mortality rate in China.The development of therapeutic drugs is the current research focus.Dai-Bai-Jie is a traditional medicine of the Dai nationality,which is commonly used in the treatment of decreasing swelling,alleviating pain and detoxification.Most of the current researches focused on the component analysis of Dai-Bai-Jie,but few researches studied on its antitumor and pharmacological effect.In this study,we incubated A549 cells with different concentrations of Dai-Bai-Jie.The cell proliferation experiment showed that the DaiBai-Jie solution inhibited the proliferation of A549 cells and caused cell apoptosis.In this work,we confirmed that Dai-Bai-Jie had an inhibitory effect on the proliferation and migration of non-small cell lung cancer A549,which may be used as a novel candidate of anti-tumor therapy for lung cancer patients.     

5-氟脲嘧啶的D-氨基葡萄糖衍生物的合成及其抗肿瘤活性的研究

以α-氨基酸为连接基,将5-氟脲嘧啶同D-氨基葡萄糖键连合成了4种新的5-氟脲嘧啶的衍生物,并确认了它们的结构。体外抗肿瘤活性实验结果表明:链连的D-氨基葡萄糖使5-氟脲嘧啶的抗肿瘤活性有明显的提高,表明它们之间可能存在着某种抗肿瘤的协同作用。     

Design and Synthesis of 2‐(5‐Phenylindol‐3‐yl)benzimidazole Derivatives with Antiproliferative Effects towards Triple‐Negative Breast Cancer Cells by Activation of ROS‐Mediated Mitochondria Dysfunction

Benzimidazole derivatives are widely studied because of their broad‐spectrum biological activity, such as antitumor properties and excellent fluorescence performance. Herein, two types of 2‐(5‐phenylindol‐3‐yl)benzimidazole derivatives ( 1 a – 1 h and 2 a – 2 e ) were rationally designed and synthesized. When these compounds were investigated in vitro anti‐screening assays, we found that all of them possessed antitumor effect, in particular compound 1 b , which showed an outstanding antiproliferative effect on MDA‐MB‐231 cells (IC₅₀≈2.6 μm ). A study of the drug action mechanisms in cells showed that the antitumor activity of the compounds is proportional to their lipophilicity and cellular uptake; the tested compounds all entered the lysosome of MDA‐MB‐231 cells and caused changes in the levels of reactive oxygen species (ROS), and then caused mitochondrial damage. Apparent differences in the ROS levels for each compound suggest that the lethality of these compounds towards MDA‐MB‐231 cells is closely related to the ROS levels. Taken together, this study not only provides a theoretical basis for 2‐(5‐phenylindol‐3‐yl)benzimidazole anticarcinogens but also offers new thinking on the rational design of next‐generation antitumor benzimidazole derivatives.