To expand the study on the structures and biological activities of the anthracyclines anticancer drugs and reduce their toxic side effects,the new anthraquinone derivatives,9‑pyridylanthrahydrazone(9‑PAH)and 9,10‑bisp...To expand the study on the structures and biological activities of the anthracyclines anticancer drugs and reduce their toxic side effects,the new anthraquinone derivatives,9‑pyridylanthrahydrazone(9‑PAH)and 9,10‑bispyridylanthrahydrazone(9,10‑PAH)were designed and synthesized.Utilizing 9‑PAH and 9,10‑PAH as promising anticancer ligands,their respective copper complexes,namely[Cu(L1)Cl_(2)]Cl(1)and{[Cu_(4)(μ_(2)‑Cl)_(3)Cl_(4)(9,10‑PAH)_(2)(DMSO)_(2)]Cl_(2)}_(n)(2),were subsequently synthesized,where the new ligand L1 is formed by coupling two 9‑PAH ligands in the coordination reaction.The chemical and crystal structures of 1 and 2 were elucidated by IR,MS,elemental analysis,and single‑crystal X‑ray diffraction.Complex 1 forms a mononuclear structure.L1 coordinates with Cu through its three N atoms,together with two Cl atoms,to form a five‑coordinated square pyramidal geometry.Complex 2 constitutes a polymeric structure,wherein each structural unit centrosymmetrically encompasses two five‑coordinated binuclear copper complexes(Cu1,Cu2)of 9,10‑PAH,with similar square pyramidal geometry.A chlorine atom(Cl_(2)),located at the symmetry center,bridges Cu1 and Cu1A to connect the two binuclear copper structures.Meanwhile,the two five‑coordinated Cu2 atoms symmetrically bridge the adjacent structural units via one coordinated Cl atom,respectively,thus forming a 1D chain‑like polymeric structure.In vitro anticancer activity assessments revealed that 1 and 2 showed significant cytotoxicity even higher than cisplatin.Specifically,the IC_(50)values of 2 against HeLa‑229 and SK‑OV‑3 cancer cell lines were determined to be(5.92±0.32)μmol·L^(-1)and(6.48±0.39)μmol·L^(-1),respectively.2 could also block the proliferation of HeLa‑229 cells in S phase and significantly induce cell apoptosis.In addition,fluorescence quenching competition experiments suggested that 2 might interact with DNA by an intercalative binding mode,offering insights into its underlying anticancer mechanism.CCDC:2388918,1;2388919,2.展开更多
Lonicera caerulea L.fruit is an excellent source of bioactive compounds.An efficient separation method of cyanins is important for the development of many value-added products and functional food ingredients.High-spee...Lonicera caerulea L.fruit is an excellent source of bioactive compounds.An efficient separation method of cyanins is important for the development of many value-added products and functional food ingredients.High-speed counter-current chromatography(HSCCC) was applied to isolate cyanins from Lonicera caerulea fruits with a biphasic solvent system composed of methyl tert-butyl ether/n-butanol/acetonitrile/water/trifluoroacetic acid(2:2:1:5:0.01,volume ratio).1.41 mg of cyanidin 3,5-O-diglucoside,1.08 mg of cyanidin 3-O-rutinoside and 6.38 mg of cyanidin 3-O-glucoside were obtained from 40 mg of crude extract.The purities of these compounds were 95.8%,92.4% and 97.6%,respectively,as identified by high-performance liquid chromatography–diode array detection(HPLC-DAD) and high-performance liquid chromatography-electrospray ionization mass spectrometryn(HPLC-ESI/MSn).In addition,the dominant anthocyanin,cyanidin 3-O-glucoside was demonstrated cytotoxic response of human hepatocarcinoma SMMC-7721 cells,inducing live cancer cell apoptotic by flow cytometric analysis.展开更多
OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactio...OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.展开更多
OBJECTIVE To evaluate the anticancer activity of andrographolide(AGP)and its semisynthetic analogues(SRJ09and SRJ23)in pancreatic adenocarcinoma(PDAC)cell lines harbouring therapeutically highly relevant oncogenic K-r...OBJECTIVE To evaluate the anticancer activity of andrographolide(AGP)and its semisynthetic analogues(SRJ09and SRJ23)in pancreatic adenocarcinoma(PDAC)cell lines harbouring therapeutically highly relevant oncogenic K-ras glycine-12(KRAS-G12)mutant proteins.In a landmark publication,we revealed that AGP and its derivatives bind KRAS protein to inhibit RAS signaling PNAS,110:10201-06).This discovery prompted the initiation of this investigation.METHODS The cell growth inhibitory effect of the compounds on PDAC cell lines〔PANC-1(KRAS-G12D),Capan-2(KRAS-G12V),and MIA PaCa-2(KRASG12C)〕,was assessed by MTT assay.RESULTS In comparison with AGP and SRJ09,SRJ23 showed the greatest growth inhibition in all PDAC cell lines with mutant KRAS proteins.The inhibitory effect of SRJ23 on the cell growth was similar for all PDAC cell lines.AGP exerted selective growth inhibition against PANC-1(KRAS-G12D)cells,while the growth inhibition of SRJ09 was selective towards Capan-2(KRAS-G12V)cells.CONCLUSION AGP and SRJ09 showed selectivity for PDAC cell lines with specific KRAS mutations.This suggests the mutational status of KRAS protein and the structural features of these two compounds orchestrally determined the magnitude of cell growth inhibition in PDAC cell lines.The higher potency of SRJ23 implies it could be developed into an anticancer agent for the treatment of mutant KRAS-driven malignancies.To this end,efforts are in progress to derive new molecules from this compound for further improvement of potency.展开更多
ABSTRACT In an attempt at a rational design for anticancer drugs, two new potential anticancer compounds related to mitoxantrone were prepared. Compounds 4. 1.4-dihydroxy-6-aminoethyl-9.10-anthracenedione was synthesi...ABSTRACT In an attempt at a rational design for anticancer drugs, two new potential anticancer compounds related to mitoxantrone were prepared. Compounds 4. 1.4-dihydroxy-6-aminoethyl-9.10-anthracenedione was synthesized in 6 steps starting with 4-methyl-phthalic acid, and compound 5, 2(4-aminobutyl)-l 4-dihvdroxv-9,10-anthracenedione was synthesized in 5 steps from N-3-bromopropylphthalimide.展开更多
Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotec...Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.Drugs can be encapsulated or attached to the nanomaterials such as lipids,polymers and solid-core nanoparticles.In the present study,porous inorganic nanoparticles have been utilized for delivery of water-insoluble anticancer drugs.The synthesized nanoparticles were functionalized with different organic polymers.The porous nanoparticles were readily internalized by human glioblastoma U-87 MG cells,and didn′t display cytotoxicity.The internalized nanoparticles were mainly localized in endosomes/lysosomes in cells.With the hydrophobic curcumin and carfilzomib as model drugs,intracellular delivery of hydrophobic anticancer drugs by the porous inorganic nanoparticles was studied.The porous nanoparticle-based encapsulation of hydrophobic drug provides the aqueous dispersion of the drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity were significantly higher for drug loaded nanoparticles than free drug.These results suggested porous inorganic nanoparticles might be a promising intracellular carrier for hydrophobic anticancer drugs.展开更多
The availability of chemical and biological data presented in this paper is the basis for understanding not only the current state of anti-cancer drugs based on gold(Ⅲ),but also the rationale for strategies for futur...The availability of chemical and biological data presented in this paper is the basis for understanding not only the current state of anti-cancer drugs based on gold(Ⅲ),but also the rationale for strategies for future drug design.New Au(Ⅲ)nanosized complexes of cefotaxime(ceph-3)and cefepime(ceph-4)ligands as a 3rd and 4th of cephalosporin generation drugs were synthesized.Gold(Ⅲ)complexes were discussed based on the elemental,molar conductance,thermal and magnetic moment measurements as well as spectral(FTIR,1HNMR,UV-Vis,and XRD)techniques.FT-IR spectra revealed that the ceph-3 and ceph-4 ligands reacted as a bidentate ligands through carboxylate oxygen andβ-lactam oxygen groups.The analytical analysis confirm that the molar ratio is 1∶1(Au 3+/ceph)with general formula[Au(L)(Cl)2]where L=ceph-3 or ceph-4.The structures of Au(Ⅲ)complexes were presence as a square planar geometry.X-ray diffraction patterns referred to a crystalline nature for all synthesized complexes.TEM analyses confirmed that the synthetic gold(Ⅲ)complexes have a nanosized particles.In vitro antimicrobial activities of Au(Ⅲ)complexes were evaluated towards two types of bacteria(G+&G-).The antitumor activities of gold(Ⅲ)complexes are appraised against breast(MCF-7)and colorectal adenocarcinoma(Caco-2)cell lines,which means that the two complexes may consider promising anticancer drugs.展开更多
We embarked on the discovery of anticancer agents from andrographolide nearly 15 years ago.Thus far,a few lead semisynthetic compounds have been identified,but only recently we managed to pinpoint their potential mole...We embarked on the discovery of anticancer agents from andrographolide nearly 15 years ago.Thus far,a few lead semisynthetic compounds have been identified,but only recently we managed to pinpoint their potential molecular target.Through in silico and cell-based studies,these lead molecules have been found to bind K-ras oncoprotein and disrupt its function.Further molecular docking analysis suggested the compounds targeted both wild-type and oncogenic mutant K-ras.However,the binding affinity was greater for the oncogenic protein.Low binding energies to wild-type K-ras protein suggested transient binding and inhibition.The compounds showed stronger binding interactions to all three mutant K-ras proteins(G12V,G12 Cand G12D)with average free energies(ΔG bind)of-82kcal·mol-1 as compared with-61kcal·mol-1 for the wild-type protein.It is noteworthy that the binding pocket in wild-type K-ras protein,however,is different from that of the mutant proteins.SRJ23,one of the lead compounds,showed the strongest binding interactions to all three mutant K-ras proteins.Stronger binding to the mutant proteins could lead to more targeted and prolonged inhibition.Investigation into the effect of the compounds on RAS-MAPK pathway showed this pathway was disrupted in colon,breast and prostate cancer cells.In vivo studies revealed the compounds retarded the growth of human colon(HCT-116)and prostate(PC-3)cancer xenografts in mice.All of the above prompted us to synthesise derivatives of the lead compounds for improvement of binding affinity for the oncogenic K-ras.A preliminary in silico exploration found some compounds with such property and these compounds are presently undergoing extensive pharmacological investigations.展开更多
Cardiovascular diseases,cancer,diabetes and neurodegenerative diseases are four major life threatening and health damaging diseases that affect a large portion of the world population at present.Although these disease...Cardiovascular diseases,cancer,diabetes and neurodegenerative diseases are four major life threatening and health damaging diseases that affect a large portion of the world population at present.Although these diseases differ significantly in terms of symptoms and pathogeneses,they have one thing in common-a defect in the process of programmed cell death,mainly apoptosis.For example,resistance to apoptosis results in cancer formation.On the other hand,over-activation of apoptosis in endothelial cells leads to dysfunction of vascular system which can contribute to cardiovascular diseases and complications of diabetes.Therefore,understanding what causes the defects of apoptosis in those disease-related cells will provide new insights in designing target-specific therapies to treat those diseases.In order to develop a method of realtime detection of apoptosis within the target cells,we genetically engineered a fluorescence resonance energy transfer(FRET)-based biosensor.When this biosensor is synthesized in the transfected cells,the sensor protein can detect caspase activation-mediated apoptosis by changing the color from green to blue.We have generated a bank of 32 sensor cell lines consisting of various types of cancer and non-cancerous cells.We also integrated these sensor cells into six model systems including a sensor cell-based high throughput drug screening assay,3Din vitro tumor model,co-culture system,microfluidic system,zebrafish cancer model and xenograft tumor mouse models.In this talk,I will discuss the applications of these sensor cells and model systems in discovering new anti-cancer agents and elucidating the survival mechanisms of metastatic cancer cells in circulation.展开更多
OBJECTIVE To investigate the mechanism of anticancer effect of 2-methoxystypandrone(2-MS),a natural naphthoquinone isolated from Polygonum cuspidatum Sieb.et Zucc.METHODSThree types of cancer cells were investigated i...OBJECTIVE To investigate the mechanism of anticancer effect of 2-methoxystypandrone(2-MS),a natural naphthoquinone isolated from Polygonum cuspidatum Sieb.et Zucc.METHODSThree types of cancer cells were investigated in the research(A549,MCF7,B16-F10).Flow cytometer was used to determine ROS/RNS generation.Western blotting was used to detect related protein expression.Apoptosis assay,GSH/GSSG(reduced glutathione/oxidized glutathione)assay were performed using commercial kit.SiRNA knockdown was used to silence cj-un N-terminal kinase(JNK)and iNOS.High-performance liquid chromatography(HPLC)was used to detect the direct reaction of 2-MS with GSH.RESULTS 2-MS induced cytotoxity towards a panel of cancer cells,with less effect on normal cells.2-MS induced necroptosis in A549 cell and apoptosis in B16-F10 and MCF7cells.2-MS increased phosphorylation of JNK in three types of cancer cells.Inhibition of JNK with SP600125 or silencing JNK attenuated 2-MS-induced cell death.JNK also activated iNOS expression and led to nitric oxide(NO)generation in three cancer cells.NO-induced nitrative stress was responsible for DNA damage and necroptosis in A549 cells.NO also inhibited NF-κB expression and induced intrinsic apoptosis in B16-F10 and MCF7cells.Both NO scavenger hemoglobin and silencing iNOS can partially reverse 2-MS-induced cell death.Furthermore,we found that all of these were attributed to induction of hydrogen peroxide(H2O2),which was caused by glutathione(GSH)depletion through interaction of 2-MS with GSH.The interaction was validated through cell-free HPLC analysis.Both the H2O2 scavenger catalase and exogenous GSH can significantly reverse the 2-MS-induced cell death.But catalase did not protect against the decrease in GSH level.In contrast,there showed no clear increase of both H2O2 and NO in non-carcinoma liver cell LO2.CONCLUSION Taken together,a medicinal plant-derived 1,4-napthoquinone,induced iNOS expression by H2O2-dependent JNK activation,caused nitrative stress,finally led to cancer cell death by necroptosis or apoptosis.展开更多
文摘To expand the study on the structures and biological activities of the anthracyclines anticancer drugs and reduce their toxic side effects,the new anthraquinone derivatives,9‑pyridylanthrahydrazone(9‑PAH)and 9,10‑bispyridylanthrahydrazone(9,10‑PAH)were designed and synthesized.Utilizing 9‑PAH and 9,10‑PAH as promising anticancer ligands,their respective copper complexes,namely[Cu(L1)Cl_(2)]Cl(1)and{[Cu_(4)(μ_(2)‑Cl)_(3)Cl_(4)(9,10‑PAH)_(2)(DMSO)_(2)]Cl_(2)}_(n)(2),were subsequently synthesized,where the new ligand L1 is formed by coupling two 9‑PAH ligands in the coordination reaction.The chemical and crystal structures of 1 and 2 were elucidated by IR,MS,elemental analysis,and single‑crystal X‑ray diffraction.Complex 1 forms a mononuclear structure.L1 coordinates with Cu through its three N atoms,together with two Cl atoms,to form a five‑coordinated square pyramidal geometry.Complex 2 constitutes a polymeric structure,wherein each structural unit centrosymmetrically encompasses two five‑coordinated binuclear copper complexes(Cu1,Cu2)of 9,10‑PAH,with similar square pyramidal geometry.A chlorine atom(Cl_(2)),located at the symmetry center,bridges Cu1 and Cu1A to connect the two binuclear copper structures.Meanwhile,the two five‑coordinated Cu2 atoms symmetrically bridge the adjacent structural units via one coordinated Cl atom,respectively,thus forming a 1D chain‑like polymeric structure.In vitro anticancer activity assessments revealed that 1 and 2 showed significant cytotoxicity even higher than cisplatin.Specifically,the IC_(50)values of 2 against HeLa‑229 and SK‑OV‑3 cancer cell lines were determined to be(5.92±0.32)μmol·L^(-1)and(6.48±0.39)μmol·L^(-1),respectively.2 could also block the proliferation of HeLa‑229 cells in S phase and significantly induce cell apoptosis.In addition,fluorescence quenching competition experiments suggested that 2 might interact with DNA by an intercalative binding mode,offering insights into its underlying anticancer mechanism.CCDC:2388918,1;2388919,2.
基金Project(KSCX2-YW-N-043)supported by the Knowledge Innovation Program of the Chinese Academy of Sciences,China
文摘Lonicera caerulea L.fruit is an excellent source of bioactive compounds.An efficient separation method of cyanins is important for the development of many value-added products and functional food ingredients.High-speed counter-current chromatography(HSCCC) was applied to isolate cyanins from Lonicera caerulea fruits with a biphasic solvent system composed of methyl tert-butyl ether/n-butanol/acetonitrile/water/trifluoroacetic acid(2:2:1:5:0.01,volume ratio).1.41 mg of cyanidin 3,5-O-diglucoside,1.08 mg of cyanidin 3-O-rutinoside and 6.38 mg of cyanidin 3-O-glucoside were obtained from 40 mg of crude extract.The purities of these compounds were 95.8%,92.4% and 97.6%,respectively,as identified by high-performance liquid chromatography–diode array detection(HPLC-DAD) and high-performance liquid chromatography-electrospray ionization mass spectrometryn(HPLC-ESI/MSn).In addition,the dominant anthocyanin,cyanidin 3-O-glucoside was demonstrated cytotoxic response of human hepatocarcinoma SMMC-7721 cells,inducing live cancer cell apoptotic by flow cytometric analysis.
基金The project supported by Macao Science and Technology Development Fund(014/2014/A1)
文摘OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.
基金The project supported by Ministry of Education,Malaysia(Research University Grant Scheme Grant 04-02-12-2017RUFundamental Research Grant Scheme Grant 04-02-13-1324FR)
文摘OBJECTIVE To evaluate the anticancer activity of andrographolide(AGP)and its semisynthetic analogues(SRJ09and SRJ23)in pancreatic adenocarcinoma(PDAC)cell lines harbouring therapeutically highly relevant oncogenic K-ras glycine-12(KRAS-G12)mutant proteins.In a landmark publication,we revealed that AGP and its derivatives bind KRAS protein to inhibit RAS signaling PNAS,110:10201-06).This discovery prompted the initiation of this investigation.METHODS The cell growth inhibitory effect of the compounds on PDAC cell lines〔PANC-1(KRAS-G12D),Capan-2(KRAS-G12V),and MIA PaCa-2(KRASG12C)〕,was assessed by MTT assay.RESULTS In comparison with AGP and SRJ09,SRJ23 showed the greatest growth inhibition in all PDAC cell lines with mutant KRAS proteins.The inhibitory effect of SRJ23 on the cell growth was similar for all PDAC cell lines.AGP exerted selective growth inhibition against PANC-1(KRAS-G12D)cells,while the growth inhibition of SRJ09 was selective towards Capan-2(KRAS-G12V)cells.CONCLUSION AGP and SRJ09 showed selectivity for PDAC cell lines with specific KRAS mutations.This suggests the mutational status of KRAS protein and the structural features of these two compounds orchestrally determined the magnitude of cell growth inhibition in PDAC cell lines.The higher potency of SRJ23 implies it could be developed into an anticancer agent for the treatment of mutant KRAS-driven malignancies.To this end,efforts are in progress to derive new molecules from this compound for further improvement of potency.
文摘ABSTRACT In an attempt at a rational design for anticancer drugs, two new potential anticancer compounds related to mitoxantrone were prepared. Compounds 4. 1.4-dihydroxy-6-aminoethyl-9.10-anthracenedione was synthesized in 6 steps starting with 4-methyl-phthalic acid, and compound 5, 2(4-aminobutyl)-l 4-dihvdroxv-9,10-anthracenedione was synthesized in 5 steps from N-3-bromopropylphthalimide.
基金Science and Technology Development Fund,Macao SAR(0168/2019/A3)。
文摘Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.Drugs can be encapsulated or attached to the nanomaterials such as lipids,polymers and solid-core nanoparticles.In the present study,porous inorganic nanoparticles have been utilized for delivery of water-insoluble anticancer drugs.The synthesized nanoparticles were functionalized with different organic polymers.The porous nanoparticles were readily internalized by human glioblastoma U-87 MG cells,and didn′t display cytotoxicity.The internalized nanoparticles were mainly localized in endosomes/lysosomes in cells.With the hydrophobic curcumin and carfilzomib as model drugs,intracellular delivery of hydrophobic anticancer drugs by the porous inorganic nanoparticles was studied.The porous nanoparticle-based encapsulation of hydrophobic drug provides the aqueous dispersion of the drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity were significantly higher for drug loaded nanoparticles than free drug.These results suggested porous inorganic nanoparticles might be a promising intracellular carrier for hydrophobic anticancer drugs.
基金the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University,through the Research Funding Program(#RFP-1440-3)。
文摘The availability of chemical and biological data presented in this paper is the basis for understanding not only the current state of anti-cancer drugs based on gold(Ⅲ),but also the rationale for strategies for future drug design.New Au(Ⅲ)nanosized complexes of cefotaxime(ceph-3)and cefepime(ceph-4)ligands as a 3rd and 4th of cephalosporin generation drugs were synthesized.Gold(Ⅲ)complexes were discussed based on the elemental,molar conductance,thermal and magnetic moment measurements as well as spectral(FTIR,1HNMR,UV-Vis,and XRD)techniques.FT-IR spectra revealed that the ceph-3 and ceph-4 ligands reacted as a bidentate ligands through carboxylate oxygen andβ-lactam oxygen groups.The analytical analysis confirm that the molar ratio is 1∶1(Au 3+/ceph)with general formula[Au(L)(Cl)2]where L=ceph-3 or ceph-4.The structures of Au(Ⅲ)complexes were presence as a square planar geometry.X-ray diffraction patterns referred to a crystalline nature for all synthesized complexes.TEM analyses confirmed that the synthetic gold(Ⅲ)complexes have a nanosized particles.In vitro antimicrobial activities of Au(Ⅲ)complexes were evaluated towards two types of bacteria(G+&G-).The antitumor activities of gold(Ⅲ)complexes are appraised against breast(MCF-7)and colorectal adenocarcinoma(Caco-2)cell lines,which means that the two complexes may consider promising anticancer drugs.
文摘We embarked on the discovery of anticancer agents from andrographolide nearly 15 years ago.Thus far,a few lead semisynthetic compounds have been identified,but only recently we managed to pinpoint their potential molecular target.Through in silico and cell-based studies,these lead molecules have been found to bind K-ras oncoprotein and disrupt its function.Further molecular docking analysis suggested the compounds targeted both wild-type and oncogenic mutant K-ras.However,the binding affinity was greater for the oncogenic protein.Low binding energies to wild-type K-ras protein suggested transient binding and inhibition.The compounds showed stronger binding interactions to all three mutant K-ras proteins(G12V,G12 Cand G12D)with average free energies(ΔG bind)of-82kcal·mol-1 as compared with-61kcal·mol-1 for the wild-type protein.It is noteworthy that the binding pocket in wild-type K-ras protein,however,is different from that of the mutant proteins.SRJ23,one of the lead compounds,showed the strongest binding interactions to all three mutant K-ras proteins.Stronger binding to the mutant proteins could lead to more targeted and prolonged inhibition.Investigation into the effect of the compounds on RAS-MAPK pathway showed this pathway was disrupted in colon,breast and prostate cancer cells.In vivo studies revealed the compounds retarded the growth of human colon(HCT-116)and prostate(PC-3)cancer xenografts in mice.All of the above prompted us to synthesise derivatives of the lead compounds for improvement of binding affinity for the oncogenic K-ras.A preliminary in silico exploration found some compounds with such property and these compounds are presently undergoing extensive pharmacological investigations.
文摘Cardiovascular diseases,cancer,diabetes and neurodegenerative diseases are four major life threatening and health damaging diseases that affect a large portion of the world population at present.Although these diseases differ significantly in terms of symptoms and pathogeneses,they have one thing in common-a defect in the process of programmed cell death,mainly apoptosis.For example,resistance to apoptosis results in cancer formation.On the other hand,over-activation of apoptosis in endothelial cells leads to dysfunction of vascular system which can contribute to cardiovascular diseases and complications of diabetes.Therefore,understanding what causes the defects of apoptosis in those disease-related cells will provide new insights in designing target-specific therapies to treat those diseases.In order to develop a method of realtime detection of apoptosis within the target cells,we genetically engineered a fluorescence resonance energy transfer(FRET)-based biosensor.When this biosensor is synthesized in the transfected cells,the sensor protein can detect caspase activation-mediated apoptosis by changing the color from green to blue.We have generated a bank of 32 sensor cell lines consisting of various types of cancer and non-cancerous cells.We also integrated these sensor cells into six model systems including a sensor cell-based high throughput drug screening assay,3Din vitro tumor model,co-culture system,microfluidic system,zebrafish cancer model and xenograft tumor mouse models.In this talk,I will discuss the applications of these sensor cells and model systems in discovering new anti-cancer agents and elucidating the survival mechanisms of metastatic cancer cells in circulation.
基金The project supported by the Science and Technology Development Fund,Macao S.A.R(FDCT)(021/2012/A1)the Research Fund of University of Macao(MYRG118〔(Y2-L4)-ICMS13-CXP〕
文摘OBJECTIVE To investigate the mechanism of anticancer effect of 2-methoxystypandrone(2-MS),a natural naphthoquinone isolated from Polygonum cuspidatum Sieb.et Zucc.METHODSThree types of cancer cells were investigated in the research(A549,MCF7,B16-F10).Flow cytometer was used to determine ROS/RNS generation.Western blotting was used to detect related protein expression.Apoptosis assay,GSH/GSSG(reduced glutathione/oxidized glutathione)assay were performed using commercial kit.SiRNA knockdown was used to silence cj-un N-terminal kinase(JNK)and iNOS.High-performance liquid chromatography(HPLC)was used to detect the direct reaction of 2-MS with GSH.RESULTS 2-MS induced cytotoxity towards a panel of cancer cells,with less effect on normal cells.2-MS induced necroptosis in A549 cell and apoptosis in B16-F10 and MCF7cells.2-MS increased phosphorylation of JNK in three types of cancer cells.Inhibition of JNK with SP600125 or silencing JNK attenuated 2-MS-induced cell death.JNK also activated iNOS expression and led to nitric oxide(NO)generation in three cancer cells.NO-induced nitrative stress was responsible for DNA damage and necroptosis in A549 cells.NO also inhibited NF-κB expression and induced intrinsic apoptosis in B16-F10 and MCF7cells.Both NO scavenger hemoglobin and silencing iNOS can partially reverse 2-MS-induced cell death.Furthermore,we found that all of these were attributed to induction of hydrogen peroxide(H2O2),which was caused by glutathione(GSH)depletion through interaction of 2-MS with GSH.The interaction was validated through cell-free HPLC analysis.Both the H2O2 scavenger catalase and exogenous GSH can significantly reverse the 2-MS-induced cell death.But catalase did not protect against the decrease in GSH level.In contrast,there showed no clear increase of both H2O2 and NO in non-carcinoma liver cell LO2.CONCLUSION Taken together,a medicinal plant-derived 1,4-napthoquinone,induced iNOS expression by H2O2-dependent JNK activation,caused nitrative stress,finally led to cancer cell death by necroptosis or apoptosis.
