A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activitie...A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.展开更多
Vanadium compounds are promising anti-diabetic agents. However, the underlying mechanisms have not been fully elucidated. Inflammation and auto-immune disorders play important roles in the progresses of both type Ⅰ a...Vanadium compounds are promising anti-diabetic agents. However, the underlying mechanisms have not been fully elucidated. Inflammation and auto-immune disorders play important roles in the progresses of both type Ⅰ and type Ⅱ diabetes, in which heat shock protein 60 （HSP60） is an important endogenous inflammatory mediator. In the present work, we investigated the effects of vanadium compounds （vanadyl sulfate and sodium metavanadate） on the IL-6 production in RAW264.7 cells upon HSP60 stimulation. Our data revealed that both vanadyl ions regulated the IL-6 expression in a concentration-dependent manner. However, the two common NF-κB and PPAR-γ, signal pathways were not involved in this process. Further works are needed to elucidate the underlying mechanism and significance of the immuno-modification actions for the pharmacological applications of anti-diabetic vanadium compounds.展开更多
As a synthesized antineoplastic organoselenium compound, ethaselen is known to induce apoptosis in tumor cells via dose-dependent thioredoxin reductase （TrxR） inhibition. Thioredoxin, the multifunctional biological ...As a synthesized antineoplastic organoselenium compound, ethaselen is known to induce apoptosis in tumor cells via dose-dependent thioredoxin reductase （TrxR） inhibition. Thioredoxin, the multifunctional biological substrate of TrxR, is then left in the oxidized state, which subsequently leads to intracellular accumulation of reactive oxygen species （ROS）, cell cycle arrest and/or apoptosis. However, the low dose effect of ethaselen remains largely unknown. Several subclones have been derived from HepG2 cells by using single cell or colony isolation. The low dose of ethaselen was defined as the drug concentration of retaining 〉90% HepG2 cells alive. The HepG2 cells were used as reference of its subclones （SM01, SM02 and SM03）, and the cell cycle transition, intracellular proteins change, colony formation and sphere growth were assayed in treatment of low dose ethaselen. HepG2 and its subclones differently responded to lethal dose of cisplatin or 5-fluorouracil. Low dose of ethaselen （1 μm） modulated the cell cycle transition at 12 h of treatment, but ceils were partially recovered at 24 h of treatment though some proteins were still affected. Low dose of ethaselen did not inhibit the small colony （diameter 〉 100 μm） formation and sphere growth of HepG2 and SM01. However, low dose of ethaselen could specifically inhibit the survival, large colony （diameter 〉500 μm） formation and sphere growth of SM03, although SM03 could be rapidly recovered from ethaselen-induced cell cycle check. HepG2 and its subclone cells could survive but respond differently to treatment of low dose ethaselen （1 μM）. Low dose of ethaselen could significantly inhibit a HepG2 subclone （SM03） in cell survival and colony growth.展开更多
Ethaselen, an organoselenium compound designed and synthesized in the School of Pharmaceutical Sciences, Peking University, has been entitled to independent intellectual property rights both at home and abroad. As one...Ethaselen, an organoselenium compound designed and synthesized in the School of Pharmaceutical Sciences, Peking University, has been entitled to independent intellectual property rights both at home and abroad. As one of the novel antitumor drugs, ethaselen has been extensively studied in Phase I clinical trial, and its biological target is thioredoxin reductase. In this review, we focus on the ethaselen＇s efficacy and pharmacological actions, including antitumor effects both in vitro and in vivo, and immunologic functions. These research findings not only provide the theoretical basis for the anticancer study of ethaselen, but also guide the clinical trial of ethaselen.展开更多
By analyzing the key steps that restricted the industrial synthesis of salidroside, selective protection of tyrosol with different acylation reagents was adopted. The strategy facilitated the crystallization of interm...By analyzing the key steps that restricted the industrial synthesis of salidroside, selective protection of tyrosol with different acylation reagents was adopted. The strategy facilitated the crystallization of intermediates, which allowed the scalable synthesis of salidroside. It included a reaction of penta-O-acetyl-β-D-glucose with acyl protected tyrosol in the presence of Lewis acid catalyst（ZnCl2）, followed by deacylation under basic condition（NaOMe/MeOH） to give the salidroside. The total yield of this three-step reaction was 47%. Final product and intermediates were purified by recrystallization, which significantly reduced the cost and made the large scale synthesis feasible.展开更多
We have synthesized the novel compounds 1a-1i,which are a series of hybrid analogues to 6-benzyl-1-（benzyloxymethyl）- 5-iodouracil,a compound showing strong activity against HIV-1.We also evaluated the activity of t...We have synthesized the novel compounds 1a-1i,which are a series of hybrid analogues to 6-benzyl-1-（benzyloxymethyl）- 5-iodouracil,a compound showing strong activity against HIV-1.We also evaluated the activity of these compounds as the inhibitors of HIV-1 reverse transcriptase（HIV-1 RT）,and they have demonstrated moderate activity.展开更多
Oral lichen planus （OLP） is a chronic inflammatory disorder and premalignantlesion, of which the mechanisms are still obscure. In the present study, the expression levels of miR-96/182/183 cluster, miR-203, miR-375,...Oral lichen planus （OLP） is a chronic inflammatory disorder and premalignantlesion, of which the mechanisms are still obscure. In the present study, the expression levels of miR-96/182/183 cluster, miR-203, miR-375, and miR-769-5p in both tissues and exfoliative cells of OLP patients as well as healthy volunteers were detected, differentially expressed miRNAs were identified and their correlation with OLP was evaluated by a biplot method. Experimental results show that miR-203 is significantly up-regulated in patient lesion tissues in comparison to volunteer mucosa tissues. Moreover, the contra- dictory insignificant expression changes of miR-203 as well as miR-96/182/183 cluster in comparisons of exfoliative cell samples suggest that different cell compositions in OLP lesion have distinct miRNA regulation, which accords with the histological heterogeneity of OLP. Finally, biplot analyses indicate the expression of miR-203 and miR-96/182/183 cluster are positively correlated in patient lesions. These results provide miR-203 as a molecular indicator of heterogeneity of OLP, and also a potential diagnostic biomarker or therapeutic target that deserves further studies.展开更多
A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through se...A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through selective cyclization and nucleophilic ring-opening of cyclic carbamates. All the products showed no noticeable activity in the antibiotic test in vitro. The result suggests that the urea-linked hydroxyl-alkylamine derivatives of aminoglycosides may not be suitable structures for the enhancement of antibiotic activity.展开更多
基金Ministry of Science and Technology of China(Grant No.2012ZX09103101-042)
文摘A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.
基金National Natural Science Foundation of China(Grant No.21271012)
文摘Vanadium compounds are promising anti-diabetic agents. However, the underlying mechanisms have not been fully elucidated. Inflammation and auto-immune disorders play important roles in the progresses of both type Ⅰ and type Ⅱ diabetes, in which heat shock protein 60 （HSP60） is an important endogenous inflammatory mediator. In the present work, we investigated the effects of vanadium compounds （vanadyl sulfate and sodium metavanadate） on the IL-6 production in RAW264.7 cells upon HSP60 stimulation. Our data revealed that both vanadyl ions regulated the IL-6 expression in a concentration-dependent manner. However, the two common NF-κB and PPAR-γ, signal pathways were not involved in this process. Further works are needed to elucidate the underlying mechanism and significance of the immuno-modification actions for the pharmacological applications of anti-diabetic vanadium compounds.
基金National Natural Science Foundation(Grant No.81372266)National Science and Technology Major Project,People’s Republic of China(Grant No.2011zx09101-001-03)
文摘As a synthesized antineoplastic organoselenium compound, ethaselen is known to induce apoptosis in tumor cells via dose-dependent thioredoxin reductase （TrxR） inhibition. Thioredoxin, the multifunctional biological substrate of TrxR, is then left in the oxidized state, which subsequently leads to intracellular accumulation of reactive oxygen species （ROS）, cell cycle arrest and/or apoptosis. However, the low dose effect of ethaselen remains largely unknown. Several subclones have been derived from HepG2 cells by using single cell or colony isolation. The low dose of ethaselen was defined as the drug concentration of retaining 〉90% HepG2 cells alive. The HepG2 cells were used as reference of its subclones （SM01, SM02 and SM03）, and the cell cycle transition, intracellular proteins change, colony formation and sphere growth were assayed in treatment of low dose ethaselen. HepG2 and its subclones differently responded to lethal dose of cisplatin or 5-fluorouracil. Low dose of ethaselen （1 μm） modulated the cell cycle transition at 12 h of treatment, but ceils were partially recovered at 24 h of treatment though some proteins were still affected. Low dose of ethaselen did not inhibit the small colony （diameter 〉 100 μm） formation and sphere growth of HepG2 and SM01. However, low dose of ethaselen could specifically inhibit the survival, large colony （diameter 〉500 μm） formation and sphere growth of SM03, although SM03 could be rapidly recovered from ethaselen-induced cell cycle check. HepG2 and its subclone cells could survive but respond differently to treatment of low dose ethaselen （1 μM）. Low dose of ethaselen could significantly inhibit a HepG2 subclone （SM03） in cell survival and colony growth.
基金National Natural Science Foundation of China(Grant No.30472036)
文摘Ethaselen, an organoselenium compound designed and synthesized in the School of Pharmaceutical Sciences, Peking University, has been entitled to independent intellectual property rights both at home and abroad. As one of the novel antitumor drugs, ethaselen has been extensively studied in Phase I clinical trial, and its biological target is thioredoxin reductase. In this review, we focus on the ethaselen＇s efficacy and pharmacological actions, including antitumor effects both in vitro and in vivo, and immunologic functions. These research findings not only provide the theoretical basis for the anticancer study of ethaselen, but also guide the clinical trial of ethaselen.
基金the National Basic Research Program of China(973 Program,Grant No.2012CB822100)the National Key Technology R&D Program"New Drug Innovation"of China(Grant No.2012ZX09502001-001)the National Natural Science Foundation of China(Grant No.21232002,21072016 and 21072017)
文摘By analyzing the key steps that restricted the industrial synthesis of salidroside, selective protection of tyrosol with different acylation reagents was adopted. The strategy facilitated the crystallization of intermediates, which allowed the scalable synthesis of salidroside. It included a reaction of penta-O-acetyl-β-D-glucose with acyl protected tyrosol in the presence of Lewis acid catalyst（ZnCl2）, followed by deacylation under basic condition（NaOMe/MeOH） to give the salidroside. The total yield of this three-step reaction was 47%. Final product and intermediates were purified by recrystallization, which significantly reduced the cost and made the large scale synthesis feasible.
基金National Natural Science Foundation of China (Grant No.20672008,and 20972011)
文摘We have synthesized the novel compounds 1a-1i,which are a series of hybrid analogues to 6-benzyl-1-（benzyloxymethyl）- 5-iodouracil,a compound showing strong activity against HIV-1.We also evaluated the activity of these compounds as the inhibitors of HIV-1 reverse transcriptase（HIV-1 RT）,and they have demonstrated moderate activity.
基金National Natural Science Foundation of China(Grant No.91029711)
文摘Oral lichen planus （OLP） is a chronic inflammatory disorder and premalignantlesion, of which the mechanisms are still obscure. In the present study, the expression levels of miR-96/182/183 cluster, miR-203, miR-375, and miR-769-5p in both tissues and exfoliative cells of OLP patients as well as healthy volunteers were detected, differentially expressed miRNAs were identified and their correlation with OLP was evaluated by a biplot method. Experimental results show that miR-203 is significantly up-regulated in patient lesion tissues in comparison to volunteer mucosa tissues. Moreover, the contra- dictory insignificant expression changes of miR-203 as well as miR-96/182/183 cluster in comparisons of exfoliative cell samples suggest that different cell compositions in OLP lesion have distinct miRNA regulation, which accords with the histological heterogeneity of OLP. Finally, biplot analyses indicate the expression of miR-203 and miR-96/182/183 cluster are positively correlated in patient lesions. These results provide miR-203 as a molecular indicator of heterogeneity of OLP, and also a potential diagnostic biomarker or therapeutic target that deserves further studies.
基金National Basic Research Program(973 Program Grant No.2004CB518904)
文摘A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through selective cyclization and nucleophilic ring-opening of cyclic carbamates. All the products showed no noticeable activity in the antibiotic test in vitro. The result suggests that the urea-linked hydroxyl-alkylamine derivatives of aminoglycosides may not be suitable structures for the enhancement of antibiotic activity.
