Yao Xue Xue Bao Acta Pharmaceutica Sinica, Sep 1, 2009
LEDGF/p75 is a newly found cell cofactor, which plays an essential role in the integration of HIV... more LEDGF/p75 is a newly found cell cofactor, which plays an essential role in the integration of HIV-1 cDNA into host chromosomes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells or over-expressing the integrase-binding domain of LEDGF/p75 blocks viral replication. The essential role of LEDGF/p75 in HIV-1 replication makes it a new target for anti-HIV-1 drug development. This article reviews the function of LEDGF/p75, LEDGF/p75-integrase interaction and LEDGF/p75 inhibitors.
, the transcription factors of HIV-1, play an important role in triggering HIV transcription. The... more , the transcription factors of HIV-1, play an important role in triggering HIV transcription. The inhibition of NF-B activation and their signaling pathway offers a potential anti-HIV therapy strategy. This review reports the mode of action of NF-B in triggering HIV-1 transcription and the status of the inhibitors.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2014
the protective effects of a novel stilbene derivative, (e)-2-(3,4,5- trimethoxystyryl)-3,5,6-trim... more the protective effects of a novel stilbene derivative, (e)-2-(3,4,5- trimethoxystyryl)-3,5,6-trimethylpyrazine (MStMp), on hydrogen peroxide (h2o2)-induced human derived neuroblastoma cell (Sh-Sy5y) damage and its molecular mechanisms were investigated. Sh-Sy5y cells were exposed to 200 μmol.l-1 h2o2 for 12 h. the effect of MStMp on cell viability and apoptosis was assessed by 3-(4,5-dimethyl- thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (Mtt) assay and flow cytometry method. the activities of lactate dehydrogenase (ldh), superoxide dismutase (Sod) and nitric oxide synthetase (noS) and the content of malondialdehyde (Mda), reduced glutathione (gSh) and nitric oxide (no) in cells were determined by commercial kits. the expressions of pro-apoptotic factor caspase-3, caspase-9 and inducible noS (inoS) were detected by Western blotting. intracellular formation of reactive oxygen species (roS) was assessed using 6-carboxy-2’,7’-dichlorofluorescin diacetate (dCfh-da) fluorescent probe. ...
A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for t... more A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for their activity against human immunodeficiency virus (HIV) in MT-4 cells. Three compounds (3b, 5a, and 6a1) exhibited moderate activities against wild-type (wt) HIV-1 with EC50 values ranging from 11 to 56 μm. Among them, compound 5a was the most potent inhibitor with a novel chemical skeleton, affording a new lead compound for further molecular optimization. An enzyme assay was also implemented to confirm the binding target of the active compounds represented by 6a1. Molecular simulation studies on compound 5a, 6a1, and 7a4 were carried out to understand their binding mode with wt HIV-1 reverse transcriptase (RT) and provided useful information for further rational design of NNRTIs.
A series of 5-alkylthio (2a-d), 4-arylideneamino (3a-d) and 4-arylideneamino-5-alkylthio derivati... more A series of 5-alkylthio (2a-d), 4-arylideneamino (3a-d) and 4-arylideneamino-5-alkylthio derivatives (4a-f) of 4-amino-3-(2-furyl)-5-mercapto-1,2,4-triazole (1) were synthesized by alkylation of the parent compound with alkyl halides and condensation with aldehydes, respectively. Sulfanyl dimers 5a-d and 4-iminomethyl dimer 6 were correspondingly prepared by reaction with alkane dibromides and 1,4-diformylbenzene. Mannich base 7 was also synthesized by aminomethylation of the 3-sulfanyltriazole 1 at the N 1 position. The newly designed and synthesized substituted s-triazole derivatives were assayed for anti-HIV-1 activity by examination of their inhibition of HIV-1-induced cytopathogenicity in MT-4 cells and by determination of their inhibitory effect on HIV-1 reverse transcriptase. Compound 4e was found to be the most active inhibitor against HIV-1 replication in cell culture (EC 50 = 12 μM) and against HIV-1 reverse transcriptase (IC 50 = 43.5 μM), which provided a good lead for further optimization.
The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one 1,1-dioxide (5) was synthe... more The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one 1,1-dioxide (5) was synthesized and its novel mono N 2 -or N 4 -substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N 2 ,N 4 -disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR, 1 H-NMR, 13 C-NMR and MS spectral analysis.
International Journal of Quantum Information, 2011
ABSTRACT We propose a new protocol for deterministic secure quantum communication with a four-qub... more ABSTRACT We propose a new protocol for deterministic secure quantum communication with a four-qubit W state. In this protocol, by using four local two-particle unitary operations and Bell basis measurements, the two legitimate users can directly transmit secret messages after exchanging some additional classical information. It will be shown that our protocol has a high capacity as each W state can carry two bits of secret information, and has a high intrinsic efficiency because almost all the instances are useful. Furthermore, this protocol is feasible with present day techniques.
Regioselective Synthesis of the Novel N 4 -Substituted Pyrazolo[4,5-e][1,2,4]thiadiazines as Pote... more Regioselective Synthesis of the Novel N 4 -Substituted Pyrazolo[4,5-e][1,2,4]thiadiazines as Potent HIV-1 NNRTIs. -Starting from the pyrazole derivatives (I), the novel thiadiazine regioisomer (IV) is prepared and selectively alkylated at N4. The resulting derivatives are evaluated as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. Positive results are only observed for (VIb) and the corresponding chloro analogue. -(LIU*, X.; CHEN, N.; YAN, R.; XU, W.; MOLINA, M. T.; VEGA, S.; Heterocycles 68 (2006) 6, 1225-1232; Inst. Med. Chem., Sch. Pharm., Shandong Univ., Jinan 250012, Peop. Rep. China; Eng.) -Mais 42-164
The HIV-1 Rev protein, which traffics through nucleolus and shuttles between nucleus and cytoplas... more The HIV-1 Rev protein, which traffics through nucleolus and shuttles between nucleus and cytoplasm, facilitates export of unspliced and singly spliced viral transcripts containing RRE RNA by the CRM1 export pathway. Inhibitions of the various stages of Rev-mediated RNA transport can arrest HIV-1 transcriptional process. The current understanding to the mechanism of Rev function, Rev-RRE interaction, as well as inhibitors hereof is reviewed.
More attention is being paid to the relationship between kidney dysfunction and cardiovascular ev... more More attention is being paid to the relationship between kidney dysfunction and cardiovascular events Characteristic features include renal dysfunction, left ventricular (LV) and left atrial (LA) enlargement. The aim of this study is to evaluate the relationships between circulating levels of β2-microglobulin (β2-m) and cystatin C and left atrial size in patients with coronary artery disease. We recruited 300 patients who presented with chest tightness or chest pain and subsequently underwent coronary angiography. Of these, 202 patients were diagnosed with coronary artery disease (CAD) and 98 patients without CAD (non-CAD). Laboratory measurements included liver, kidney function (urea nitrogen, creatinine, β2-m and cystatin C), fasting glucose, and lipid analysis. CrCl were calculated according to Cockroft-Gault formula. Echocardiology was used to evaluate the cardiac structure and function. Significant differences of β2-m and cystatin C exist and no difference of creatinine and CrCl existed between the two groups. LA diameters were positively related to circulating levels of β2-m in the CAD group (r = 0.452, p < 0.001) and non-CAD group (r = 0.360, p < 0.001), and the similar relationships between LAD and circulating levels of cystatin C in the CAD group (r = 0.302, p < 0.001) and non-CAD group (r = 0.243, p = 0.016). LA diameters were negatively related to CrCl in both groups. After multivariate logistic regression analysis, the data indicated that the independent cardiovascular risk factors of LA enlargement for the patients with CAD were age, BMI, systolic blood pressure, LV mass, LVEDD, E/A, Em/Am, CrCl, and circulating levels of β2-m (OR = 1.630, 95% CI: 1.115 - 2.384, p = 0.012), cystatin C (OR = 4.504, 95% CI: 1.478 - 13.726, p = 0.008). A linear correlation exists between circulating levels of β2-m or cystatin C and LA diameters. Higher circulating levels of β2-m or cystatin C are independent cardiovascular risk factors of LA enlargement in patients with CAD, and could be a link between the kidney and the heart.
To investigate the effect of the H-2K d gene on the lymphocyte membrane, we constructed a small i... more To investigate the effect of the H-2K d gene on the lymphocyte membrane, we constructed a small interfering RNA (siRNA) that targets the H-2K d gene and compared the cytotoxicity of mouse lymphokine-activated killer (LAK) cells with different H-2K d expression states. H-2K d -targeting siRNA was transfected into spleen lymphocytes of BALB/C mice. Flow cytometry (FCM) was then performed to examine the expression of the H-2K d gene in the transfected and control cells. Additionally, the cytotoxicity of the transfected cells toward the H22 and K562 cell lines was evaluated in vitro using the LDH release assay. H-2K d -targeting siRNA significantly reduced the expression levels of the target protein, whereas pure transMessenger and non-silencing siRNA did not inhibit H-2K d expression at the concentrations tested. The cytotoxicity of siRNA-treated LAK cells toward H22 and K562 cells was reduced significantly. The knockdown of H-2K d gene expression by siRNA may be associated with LAK cell cytotoxicity toward neoplasm cell lines.
A series of novel 2-acyloxymethyl-3,5,6-trimethylpyrazine derivatives was designed and synthesize... more A series of novel 2-acyloxymethyl-3,5,6-trimethylpyrazine derivatives was designed and synthesized. Most compounds were found to be 1.5-4.5-fold higher potency than tetramethylpyrazine (TMP) in stimulating the proliferation of normal vascular endothelial cells and in protecting against hyperoxic acute injury. The most active one is the 2-nicotinoyl ester 5a exhibiting the maximum proliferation rate (P max ) of 88.57% at the concentration of 0.1 mmol L À1 . Structure-activity relationships of these compounds were discussed. #
A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their p... more A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.
Diarylpyrimidine and diaryltriazine derivatives, two representative structurally related classes ... more Diarylpyrimidine and diaryltriazine derivatives, two representative structurally related classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with robust potencies against wild-type and several mutant strains of HIV-1, have attracted more and more attention in the last decade. However, they have been suffering from poor aqueous solubility. A series of novel diarylpyrimidines and diaryltriazines with solubilizing substituents attached to the central rings were reported as potent NNRTIs in the patent US20140378443A1. Some compounds exhibited potencies against wild-type HIV-1 which were comparable or even superior to those of dapivirine, etravirine and rilpivirine. In addition, dramatically enhanced solubilities were observed for these new compounds. Moreover, some structure optimization strategies for improving aqueous solubility are detailed in this review, providing new insights into development of next-generation NNRTIs endowed with favorable solubility. We ant...
With continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a serie... more With continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV- 1 strain with EC50 values ranging from 0.059 μM to 1.41 μM in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 μM and 0.073 μM against wt HIV-1 respectively, which was much more effective than the control drug Nevirapine (EC50 = 0.26 μM) and comparable to Delavirdine (EC50 = 0.038 μM). In addition, one selected compound showed remarkable reverse transcriptase inhibitory activity compared to Nevirapine and Etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular...
LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a... more LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a broad spectrum of key cellular processes, and its activity is often altered under pathological conditions. LSD1 inhibitors are considered to be candidates for therapy of cancer, viral diseases and neurodegeneration. Many LSD1 inhibitors with various scaffolds have been disclosed, and a few potent molecules are in different stages of clinical development. In this review, we summarize recent biological findings on the roles of LSD1 and the current understanding of the clinical significance of LSD1, and focus on the medicinal chemistry strategies used in the design and development of LSD1 inhibitors as drug-like epigenetic modulators since 2012, including a brief consideration of structure-activity relationships.
Although recent progress in highly active antiretroviral therapy (HAART) has provided an effectiv... more Although recent progress in highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the emergence of drug-resistant HIV-1 strains and drug toxicity during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the nuclear import process of the HIV pre-integration complex (PIC). The ability of HIV-1 using host cell nuclear import machinery to translocate the viral PIC into the cell nucleus is the critical determinant in the replication of the virus in non-dividing cells, such as macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for novel anti-HIV development. In this review, we will describe the mechanisms of HIV-1 PIC translocation into the nucleus and the structure-function of the viral and cellular factors involved in this process, as well as several classes of novel anti-HIV compounds which target the nuclear import of HIV-1 PIC and effectively block viral replication.
Yao Xue Xue Bao Acta Pharmaceutica Sinica, Sep 1, 2009
LEDGF/p75 is a newly found cell cofactor, which plays an essential role in the integration of HIV... more LEDGF/p75 is a newly found cell cofactor, which plays an essential role in the integration of HIV-1 cDNA into host chromosomes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells or over-expressing the integrase-binding domain of LEDGF/p75 blocks viral replication. The essential role of LEDGF/p75 in HIV-1 replication makes it a new target for anti-HIV-1 drug development. This article reviews the function of LEDGF/p75, LEDGF/p75-integrase interaction and LEDGF/p75 inhibitors.
, the transcription factors of HIV-1, play an important role in triggering HIV transcription. The... more , the transcription factors of HIV-1, play an important role in triggering HIV transcription. The inhibition of NF-B activation and their signaling pathway offers a potential anti-HIV therapy strategy. This review reports the mode of action of NF-B in triggering HIV-1 transcription and the status of the inhibitors.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2014
the protective effects of a novel stilbene derivative, (e)-2-(3,4,5- trimethoxystyryl)-3,5,6-trim... more the protective effects of a novel stilbene derivative, (e)-2-(3,4,5- trimethoxystyryl)-3,5,6-trimethylpyrazine (MStMp), on hydrogen peroxide (h2o2)-induced human derived neuroblastoma cell (Sh-Sy5y) damage and its molecular mechanisms were investigated. Sh-Sy5y cells were exposed to 200 μmol.l-1 h2o2 for 12 h. the effect of MStMp on cell viability and apoptosis was assessed by 3-(4,5-dimethyl- thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (Mtt) assay and flow cytometry method. the activities of lactate dehydrogenase (ldh), superoxide dismutase (Sod) and nitric oxide synthetase (noS) and the content of malondialdehyde (Mda), reduced glutathione (gSh) and nitric oxide (no) in cells were determined by commercial kits. the expressions of pro-apoptotic factor caspase-3, caspase-9 and inducible noS (inoS) were detected by Western blotting. intracellular formation of reactive oxygen species (roS) was assessed using 6-carboxy-2’,7’-dichlorofluorescin diacetate (dCfh-da) fluorescent probe. ...
A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for t... more A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for their activity against human immunodeficiency virus (HIV) in MT-4 cells. Three compounds (3b, 5a, and 6a1) exhibited moderate activities against wild-type (wt) HIV-1 with EC50 values ranging from 11 to 56 μm. Among them, compound 5a was the most potent inhibitor with a novel chemical skeleton, affording a new lead compound for further molecular optimization. An enzyme assay was also implemented to confirm the binding target of the active compounds represented by 6a1. Molecular simulation studies on compound 5a, 6a1, and 7a4 were carried out to understand their binding mode with wt HIV-1 reverse transcriptase (RT) and provided useful information for further rational design of NNRTIs.
A series of 5-alkylthio (2a-d), 4-arylideneamino (3a-d) and 4-arylideneamino-5-alkylthio derivati... more A series of 5-alkylthio (2a-d), 4-arylideneamino (3a-d) and 4-arylideneamino-5-alkylthio derivatives (4a-f) of 4-amino-3-(2-furyl)-5-mercapto-1,2,4-triazole (1) were synthesized by alkylation of the parent compound with alkyl halides and condensation with aldehydes, respectively. Sulfanyl dimers 5a-d and 4-iminomethyl dimer 6 were correspondingly prepared by reaction with alkane dibromides and 1,4-diformylbenzene. Mannich base 7 was also synthesized by aminomethylation of the 3-sulfanyltriazole 1 at the N 1 position. The newly designed and synthesized substituted s-triazole derivatives were assayed for anti-HIV-1 activity by examination of their inhibition of HIV-1-induced cytopathogenicity in MT-4 cells and by determination of their inhibitory effect on HIV-1 reverse transcriptase. Compound 4e was found to be the most active inhibitor against HIV-1 replication in cell culture (EC 50 = 12 μM) and against HIV-1 reverse transcriptase (IC 50 = 43.5 μM), which provided a good lead for further optimization.
The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one 1,1-dioxide (5) was synthe... more The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one 1,1-dioxide (5) was synthesized and its novel mono N 2 -or N 4 -substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N 2 ,N 4 -disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR, 1 H-NMR, 13 C-NMR and MS spectral analysis.
International Journal of Quantum Information, 2011
ABSTRACT We propose a new protocol for deterministic secure quantum communication with a four-qub... more ABSTRACT We propose a new protocol for deterministic secure quantum communication with a four-qubit W state. In this protocol, by using four local two-particle unitary operations and Bell basis measurements, the two legitimate users can directly transmit secret messages after exchanging some additional classical information. It will be shown that our protocol has a high capacity as each W state can carry two bits of secret information, and has a high intrinsic efficiency because almost all the instances are useful. Furthermore, this protocol is feasible with present day techniques.
Regioselective Synthesis of the Novel N 4 -Substituted Pyrazolo[4,5-e][1,2,4]thiadiazines as Pote... more Regioselective Synthesis of the Novel N 4 -Substituted Pyrazolo[4,5-e][1,2,4]thiadiazines as Potent HIV-1 NNRTIs. -Starting from the pyrazole derivatives (I), the novel thiadiazine regioisomer (IV) is prepared and selectively alkylated at N4. The resulting derivatives are evaluated as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. Positive results are only observed for (VIb) and the corresponding chloro analogue. -(LIU*, X.; CHEN, N.; YAN, R.; XU, W.; MOLINA, M. T.; VEGA, S.; Heterocycles 68 (2006) 6, 1225-1232; Inst. Med. Chem., Sch. Pharm., Shandong Univ., Jinan 250012, Peop. Rep. China; Eng.) -Mais 42-164
The HIV-1 Rev protein, which traffics through nucleolus and shuttles between nucleus and cytoplas... more The HIV-1 Rev protein, which traffics through nucleolus and shuttles between nucleus and cytoplasm, facilitates export of unspliced and singly spliced viral transcripts containing RRE RNA by the CRM1 export pathway. Inhibitions of the various stages of Rev-mediated RNA transport can arrest HIV-1 transcriptional process. The current understanding to the mechanism of Rev function, Rev-RRE interaction, as well as inhibitors hereof is reviewed.
More attention is being paid to the relationship between kidney dysfunction and cardiovascular ev... more More attention is being paid to the relationship between kidney dysfunction and cardiovascular events Characteristic features include renal dysfunction, left ventricular (LV) and left atrial (LA) enlargement. The aim of this study is to evaluate the relationships between circulating levels of β2-microglobulin (β2-m) and cystatin C and left atrial size in patients with coronary artery disease. We recruited 300 patients who presented with chest tightness or chest pain and subsequently underwent coronary angiography. Of these, 202 patients were diagnosed with coronary artery disease (CAD) and 98 patients without CAD (non-CAD). Laboratory measurements included liver, kidney function (urea nitrogen, creatinine, β2-m and cystatin C), fasting glucose, and lipid analysis. CrCl were calculated according to Cockroft-Gault formula. Echocardiology was used to evaluate the cardiac structure and function. Significant differences of β2-m and cystatin C exist and no difference of creatinine and CrCl existed between the two groups. LA diameters were positively related to circulating levels of β2-m in the CAD group (r = 0.452, p < 0.001) and non-CAD group (r = 0.360, p < 0.001), and the similar relationships between LAD and circulating levels of cystatin C in the CAD group (r = 0.302, p < 0.001) and non-CAD group (r = 0.243, p = 0.016). LA diameters were negatively related to CrCl in both groups. After multivariate logistic regression analysis, the data indicated that the independent cardiovascular risk factors of LA enlargement for the patients with CAD were age, BMI, systolic blood pressure, LV mass, LVEDD, E/A, Em/Am, CrCl, and circulating levels of β2-m (OR = 1.630, 95% CI: 1.115 - 2.384, p = 0.012), cystatin C (OR = 4.504, 95% CI: 1.478 - 13.726, p = 0.008). A linear correlation exists between circulating levels of β2-m or cystatin C and LA diameters. Higher circulating levels of β2-m or cystatin C are independent cardiovascular risk factors of LA enlargement in patients with CAD, and could be a link between the kidney and the heart.
To investigate the effect of the H-2K d gene on the lymphocyte membrane, we constructed a small i... more To investigate the effect of the H-2K d gene on the lymphocyte membrane, we constructed a small interfering RNA (siRNA) that targets the H-2K d gene and compared the cytotoxicity of mouse lymphokine-activated killer (LAK) cells with different H-2K d expression states. H-2K d -targeting siRNA was transfected into spleen lymphocytes of BALB/C mice. Flow cytometry (FCM) was then performed to examine the expression of the H-2K d gene in the transfected and control cells. Additionally, the cytotoxicity of the transfected cells toward the H22 and K562 cell lines was evaluated in vitro using the LDH release assay. H-2K d -targeting siRNA significantly reduced the expression levels of the target protein, whereas pure transMessenger and non-silencing siRNA did not inhibit H-2K d expression at the concentrations tested. The cytotoxicity of siRNA-treated LAK cells toward H22 and K562 cells was reduced significantly. The knockdown of H-2K d gene expression by siRNA may be associated with LAK cell cytotoxicity toward neoplasm cell lines.
A series of novel 2-acyloxymethyl-3,5,6-trimethylpyrazine derivatives was designed and synthesize... more A series of novel 2-acyloxymethyl-3,5,6-trimethylpyrazine derivatives was designed and synthesized. Most compounds were found to be 1.5-4.5-fold higher potency than tetramethylpyrazine (TMP) in stimulating the proliferation of normal vascular endothelial cells and in protecting against hyperoxic acute injury. The most active one is the 2-nicotinoyl ester 5a exhibiting the maximum proliferation rate (P max ) of 88.57% at the concentration of 0.1 mmol L À1 . Structure-activity relationships of these compounds were discussed. #
A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their p... more A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.
Diarylpyrimidine and diaryltriazine derivatives, two representative structurally related classes ... more Diarylpyrimidine and diaryltriazine derivatives, two representative structurally related classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with robust potencies against wild-type and several mutant strains of HIV-1, have attracted more and more attention in the last decade. However, they have been suffering from poor aqueous solubility. A series of novel diarylpyrimidines and diaryltriazines with solubilizing substituents attached to the central rings were reported as potent NNRTIs in the patent US20140378443A1. Some compounds exhibited potencies against wild-type HIV-1 which were comparable or even superior to those of dapivirine, etravirine and rilpivirine. In addition, dramatically enhanced solubilities were observed for these new compounds. Moreover, some structure optimization strategies for improving aqueous solubility are detailed in this review, providing new insights into development of next-generation NNRTIs endowed with favorable solubility. We ant...
With continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a serie... more With continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV- 1 strain with EC50 values ranging from 0.059 μM to 1.41 μM in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 μM and 0.073 μM against wt HIV-1 respectively, which was much more effective than the control drug Nevirapine (EC50 = 0.26 μM) and comparable to Delavirdine (EC50 = 0.038 μM). In addition, one selected compound showed remarkable reverse transcriptase inhibitory activity compared to Nevirapine and Etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular...
LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a... more LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a broad spectrum of key cellular processes, and its activity is often altered under pathological conditions. LSD1 inhibitors are considered to be candidates for therapy of cancer, viral diseases and neurodegeneration. Many LSD1 inhibitors with various scaffolds have been disclosed, and a few potent molecules are in different stages of clinical development. In this review, we summarize recent biological findings on the roles of LSD1 and the current understanding of the clinical significance of LSD1, and focus on the medicinal chemistry strategies used in the design and development of LSD1 inhibitors as drug-like epigenetic modulators since 2012, including a brief consideration of structure-activity relationships.
Although recent progress in highly active antiretroviral therapy (HAART) has provided an effectiv... more Although recent progress in highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the emergence of drug-resistant HIV-1 strains and drug toxicity during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the nuclear import process of the HIV pre-integration complex (PIC). The ability of HIV-1 using host cell nuclear import machinery to translocate the viral PIC into the cell nucleus is the critical determinant in the replication of the virus in non-dividing cells, such as macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for novel anti-HIV development. In this review, we will describe the mechanisms of HIV-1 PIC translocation into the nucleus and the structure-function of the viral and cellular factors involved in this process, as well as several classes of novel anti-HIV compounds which target the nuclear import of HIV-1 PIC and effectively block viral replication.
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