Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were pres...Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2–5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.展开更多
Here we report results of our investigations of new class of bioactive palladium compounds (AH n ) m [PdCl 4 ], which were discovered as a result of systematic study of correlations between composition, structure and ...Here we report results of our investigations of new class of bioactive palladium compounds (AH n ) m [PdCl 4 ], which were discovered as a result of systematic study of correlations between composition, structure and bioactivity of different types of platinum metals coordination compounds. For the first time we demonstrated in vivoa possibility of development of palladium compounds, which exceed cisplatin in antitumor activity and do not show immunosuppressive effects, and palladium compounds with immunostimulating and radioprotective activities. Combinations of cytostatic agents or radiation with palladium complexes lead to significant synergism of their activities and high therapeutic efficiency exceeded an efficiency of their separated use.展开更多
A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance（1H NMR） spectrometry and high resolution mass spectrometry（HRMS）. The anti...A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance（1H NMR） spectrometry and high resolution mass spectrometry（HRMS）. The anti-proliferative activities of these compounds against human colorectal earcinoma（HCT-116） and human breast cancer （MDA-MB-231） tumor cell lines were evaluated in vitro by MTT method[MTT=3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide]. The bioassay results suggest that most of the synthesized compounds have antitumor potential to HCT-116 cell line compared with MDA-MB-231 cell line. Compounds 8a, 8b, 8d, Be, 9f and 9j competitive with Sorafenib demonstrated antiproliferative activities on HCT-116 cell line.展开更多
A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the...A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.展开更多
Actinolactomycin 1, a new 2-oxonanonoidal antitumor antibiotic, was isolated from the fermentation broth of Streptomyces flavoretus 18522 through a bioassay-guided separation procedure. The structure of 1 was determ...Actinolactomycin 1, a new 2-oxonanonoidal antitumor antibiotic, was isolated from the fermentation broth of Streptomyces flavoretus 18522 through a bioassay-guided separation procedure. The structure of 1 was determined as 4,7-dihydroxy-3,9-dimethyl-2-oxonanone by the spectroscopic methods. Compound 1 inhibited the proliferation of A2780, K562, HCT-15, A549 and HeLa cells with the IC50 values of 1.4 ± 0.4 μmol/L, 8.4 ± 4.7 μmol/L, 9.4 ± 2.2 μmol/L, 15.4 ± 5.6 μmol/L and 13.7 ± 2.0 μmol/L, respectively. Flow cytometric analysis indicated that 1 could inhibit the cell cycle of tsFT210, A2780 and K562 cells mainly at the G0/G1 phase and could also induce apoptosis in K562 cells.展开更多
Methanol extract of Stellera chamaejasme L wasassessed for antitumor activity by an antitumor activebioassay against murine leukemia P388 in vivo. Thebioassay-directed separation of the extract furnishedseven diterpen...Methanol extract of Stellera chamaejasme L wasassessed for antitumor activity by an antitumor activebioassay against murine leukemia P388 in vivo. Thebioassay-directed separation of the extract furnishedseven diterpene compounds (stellerarin, stelleramacrin,gnidimacrin, pimelea factor P2, subtoxin, huratoxin,simplexin ) and two biflavanone compounds (neochemae-jasmin A and B). Among them, gnidimacrin, stellerarinand stelleramacrin (a novel compound) were found tohave high antitumor and cytotoxic activities against P388,L1210 and K562 in vivo and in vitro. The results suggestedthat the diterpene compounds were the potent anti-tumor principles of Stellera chamaejame L展开更多
Unsymmetrical bisacridines(UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione(GSH),which can be non-enzymatic and/or catalyze...Unsymmetrical bisacridines(UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione(GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSHmediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450(CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conjugates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient’s drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.展开更多
细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,...细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径,非受体酪氨酸激酶介导的Src、Bcr-Ab l和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点,统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。展开更多
文摘Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2–5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.
文摘Here we report results of our investigations of new class of bioactive palladium compounds (AH n ) m [PdCl 4 ], which were discovered as a result of systematic study of correlations between composition, structure and bioactivity of different types of platinum metals coordination compounds. For the first time we demonstrated in vivoa possibility of development of palladium compounds, which exceed cisplatin in antitumor activity and do not show immunosuppressive effects, and palladium compounds with immunostimulating and radioprotective activities. Combinations of cytostatic agents or radiation with palladium complexes lead to significant synergism of their activities and high therapeutic efficiency exceeded an efficiency of their separated use.
基金Supported by the National Natural Science Foundation of China（No.21072115） and the Student Training Programs for Innovation of Shandong University, China（No.201210422076）.
文摘A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance（1H NMR） spectrometry and high resolution mass spectrometry（HRMS）. The anti-proliferative activities of these compounds against human colorectal earcinoma（HCT-116） and human breast cancer （MDA-MB-231） tumor cell lines were evaluated in vitro by MTT method[MTT=3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide]. The bioassay results suggest that most of the synthesized compounds have antitumor potential to HCT-116 cell line compared with MDA-MB-231 cell line. Compounds 8a, 8b, 8d, Be, 9f and 9j competitive with Sorafenib demonstrated antiproliferative activities on HCT-116 cell line.
基金Supported by the National Natural Science Foundation of China(81202038)Science and Technology Innovation Foundation in Yantai University(01081)
文摘A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.
文摘Actinolactomycin 1, a new 2-oxonanonoidal antitumor antibiotic, was isolated from the fermentation broth of Streptomyces flavoretus 18522 through a bioassay-guided separation procedure. The structure of 1 was determined as 4,7-dihydroxy-3,9-dimethyl-2-oxonanone by the spectroscopic methods. Compound 1 inhibited the proliferation of A2780, K562, HCT-15, A549 and HeLa cells with the IC50 values of 1.4 ± 0.4 μmol/L, 8.4 ± 4.7 μmol/L, 9.4 ± 2.2 μmol/L, 15.4 ± 5.6 μmol/L and 13.7 ± 2.0 μmol/L, respectively. Flow cytometric analysis indicated that 1 could inhibit the cell cycle of tsFT210, A2780 and K562 cells mainly at the G0/G1 phase and could also induce apoptosis in K562 cells.
文摘Methanol extract of Stellera chamaejasme L wasassessed for antitumor activity by an antitumor activebioassay against murine leukemia P388 in vivo. Thebioassay-directed separation of the extract furnishedseven diterpene compounds (stellerarin, stelleramacrin,gnidimacrin, pimelea factor P2, subtoxin, huratoxin,simplexin ) and two biflavanone compounds (neochemae-jasmin A and B). Among them, gnidimacrin, stellerarinand stelleramacrin (a novel compound) were found tohave high antitumor and cytotoxic activities against P388,L1210 and K562 in vivo and in vitro. The results suggestedthat the diterpene compounds were the potent anti-tumor principles of Stellera chamaejame L
文摘Unsymmetrical bisacridines(UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione(GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSHmediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450(CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conjugates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient’s drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.
文摘细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径,非受体酪氨酸激酶介导的Src、Bcr-Ab l和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点,统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。
