Transition-metal catalyzed cross-coupling is one of the basic strategies for the C-C bond formation.However,it is difficult to achieve satisfactory results when terminal alkynes with electron-withdrawing group such as...Transition-metal catalyzed cross-coupling is one of the basic strategies for the C-C bond formation.However,it is difficult to achieve satisfactory results when terminal alkynes with electron-withdrawing group such as propiolate esters are used.The reason behind this might be the easy polymerization of this type of alkynes in the presence of base.A tetrahydroxydiboron and copper sulfate co-promoted cross-coupling/cyclization of propiolate esters and o-iodobenzoic acid for the facile and efficient construction of phthalides is described.Preliminary mechanism study indicates that tetrahydroxydiboron can inhibit the polymerization of propiolate esters and increase the reaction rate.This method is characterized by high regio-and stereoselectivities,mild reaction conditions,short reaction time,broad substrate scope,and excellent functional group compatibility.展开更多
Compound 209 is a newly synthesized dithiocarbamate derivative with antiproliferation activity in vitro, however, its antitumor effect in vivo and the underlying mechanisms have yet to be identified. We explored the a...Compound 209 is a newly synthesized dithiocarbamate derivative with antiproliferation activity in vitro, however, its antitumor effect in vivo and the underlying mechanisms have yet to be identified. We explored the antitumor effect of compound 209 and the possible mechanisms for its inhibition of the growth of HT-29 xenograff tumor and proliferation of HT-29 cells. Cell proliferation was evaluated with SRB assay in vitro. The results showed that compound 209 had significant antiproliferation activity on HT-29 cells. Furthermore, the xenograff HT-29 nude mouse model was used to study the antitumor effect of compound 209 in vivo. We found that compound 209 significantly inhibited tumor growth and did not cause loss of body weight or leukocytopenia. Analysis by flow cytometry indicated that compound 209 arrested HT-29 cell cycle in G~ phase. Western blotting analysis suggested that compound 209 increased the expression of p27, cyclin E, CDK2, cyclin D1 and CDK4. These results demonstrated the antitumor effect of compound 209 and its potential use as an anticancer drug.展开更多
4-Methylpiperazine-l-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride（TM208）,a newly synthesized dithiocarbamate derivative,exhibits antitumor effect in vivo with low toxicity.However,the antitumor e...4-Methylpiperazine-l-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride（TM208）,a newly synthesized dithiocarbamate derivative,exhibits antitumor effect in vivo with low toxicity.However,the antitumor effect of TM208 in combination with drugs in clinical use for cytotoxic chemotherapy has not been identified.In our study,the antitumor effects and toxicities of TM208 in combination with cisplatin（DDP）,cyclophosphamide（CTX） and 5-fluorouracil（5-Fu）,respectively,were evaluated in vivo using a transplanted solid-type hepatocarcinoma H_（22） mice model.The results suggested that 5-Fu（5 mg/kg/2d） potentiated the antitumor effect of TM208（100 mg/kg/d） with significantly higher tumor inhibition rates（P0.01） and a slight elevation of toxicity;however,DDP and CTX in combination with TM208 did not exhibit similar enhanced antitumor effect.For further investigation,we found that the TM208 and 5-Fu combination therapy led to G_2/M cell cycle arrest of tumor cells in vivo by downregulating the protein expression of cyclin Bl,cdc2,cdk7,and upregulating the expression of p21 and p53.The protein expression levels of cyclin Dl and cyclin E were also downregulated in tumor cells treated with TM208 and 5-Fu,while those of cdk4 and cdk2 remained unchanged.The change of mRNA expression level of cdc2 was consistent with that of its protein in each group,while the mRNA expression of cyclin B1 remained unchanged among each group.These results demonstrated the dosage regimen of TM208 for combination therapy and could serve as evidence for clinical use of TM208 as an antineoplastic drug.展开更多
Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibi...Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signaling and cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC50 of 22 gM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-~B signaling in LoVo cells, suggesting that IC5 could inhibit inflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane （AOM）/dextran sodium sulfate （DSS） mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.展开更多
文摘Transition-metal catalyzed cross-coupling is one of the basic strategies for the C-C bond formation.However,it is difficult to achieve satisfactory results when terminal alkynes with electron-withdrawing group such as propiolate esters are used.The reason behind this might be the easy polymerization of this type of alkynes in the presence of base.A tetrahydroxydiboron and copper sulfate co-promoted cross-coupling/cyclization of propiolate esters and o-iodobenzoic acid for the facile and efficient construction of phthalides is described.Preliminary mechanism study indicates that tetrahydroxydiboron can inhibit the polymerization of propiolate esters and increase the reaction rate.This method is characterized by high regio-and stereoselectivities,mild reaction conditions,short reaction time,broad substrate scope,and excellent functional group compatibility.
基金China International Science and Technology Cooperation Program for Key Projects (Grant No. 2008DFA31070)
文摘Compound 209 is a newly synthesized dithiocarbamate derivative with antiproliferation activity in vitro, however, its antitumor effect in vivo and the underlying mechanisms have yet to be identified. We explored the antitumor effect of compound 209 and the possible mechanisms for its inhibition of the growth of HT-29 xenograff tumor and proliferation of HT-29 cells. Cell proliferation was evaluated with SRB assay in vitro. The results showed that compound 209 had significant antiproliferation activity on HT-29 cells. Furthermore, the xenograff HT-29 nude mouse model was used to study the antitumor effect of compound 209 in vivo. We found that compound 209 significantly inhibited tumor growth and did not cause loss of body weight or leukocytopenia. Analysis by flow cytometry indicated that compound 209 arrested HT-29 cell cycle in G~ phase. Western blotting analysis suggested that compound 209 increased the expression of p27, cyclin E, CDK2, cyclin D1 and CDK4. These results demonstrated the antitumor effect of compound 209 and its potential use as an anticancer drug.
基金National High Technology Research and Development Program of China('863' Program,Grant No.2004AA2Z3783)National Natural Science Foundation(Grant No.20172006 and 20672009)
文摘4-Methylpiperazine-l-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride（TM208）,a newly synthesized dithiocarbamate derivative,exhibits antitumor effect in vivo with low toxicity.However,the antitumor effect of TM208 in combination with drugs in clinical use for cytotoxic chemotherapy has not been identified.In our study,the antitumor effects and toxicities of TM208 in combination with cisplatin（DDP）,cyclophosphamide（CTX） and 5-fluorouracil（5-Fu）,respectively,were evaluated in vivo using a transplanted solid-type hepatocarcinoma H_（22） mice model.The results suggested that 5-Fu（5 mg/kg/2d） potentiated the antitumor effect of TM208（100 mg/kg/d） with significantly higher tumor inhibition rates（P0.01） and a slight elevation of toxicity;however,DDP and CTX in combination with TM208 did not exhibit similar enhanced antitumor effect.For further investigation,we found that the TM208 and 5-Fu combination therapy led to G_2/M cell cycle arrest of tumor cells in vivo by downregulating the protein expression of cyclin Bl,cdc2,cdk7,and upregulating the expression of p21 and p53.The protein expression levels of cyclin Dl and cyclin E were also downregulated in tumor cells treated with TM208 and 5-Fu,while those of cdk4 and cdk2 remained unchanged.The change of mRNA expression level of cdc2 was consistent with that of its protein in each group,while the mRNA expression of cyclin B1 remained unchanged among each group.These results demonstrated the dosage regimen of TM208 for combination therapy and could serve as evidence for clinical use of TM208 as an antineoplastic drug.
基金National Natural Science Foundation(Grant No.81272468 and 21001011)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education
文摘Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signaling and cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC50 of 22 gM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-~B signaling in LoVo cells, suggesting that IC5 could inhibit inflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane （AOM）/dextran sodium sulfate （DSS） mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.
