RESUMO
The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.
Assuntos
Inibidores da Angiogênese , Antineoplásicos , Apoptose , Complexos de Coordenação , Fenantrolinas , Neoplasias de Mama Triplo Negativas , Apoptose/efeitos dos fármacos , Humanos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Animais , Fenantrolinas/farmacologia , Fenantrolinas/química , Fenantrolinas/síntese química , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Sinergismo Farmacológico , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
A novel chiral oxazoline copper(II)-based complex {[Cu(C13H14NO3S)2]}2 (Cu-A) was synthesized by an in situ reaction using L-methioninol, 4-hydroxyisophthalaldehyde, sodium hydroxide and copper(II) nitrate trihydrate as reactants. Its crystal structure was characterized. In vitro, Cu-A was superior to cis-dichlorodiammineplatinum (DDP) in cytotoxicity and angiogenesis inhibition. Cu-A significantly induced apoptosis of ovarian cancer cells (SKOV3) and human umbilical vein endothelial cells (HUVECs), showing significant anti-ovarian cancer and anti-angiogenesis effects. Notably, Cu-A significantly inhibits the growth of ovarian cancer in nude mice xenografted with SKOV3 cells, and it is less renal toxic than DDP. The molecular mechanism of anti-ovarian cancer and anti-angiogenesis is possibly that it down-regulates the expression of the proteins ERK1/2, AKT, FAK, and VEGFR2 and their phosphorylated proteins p-ERK1/2, p-AKT, p-FAK, and p-VEGFR2 in the VEGF/VEGFR2 signal transduction pathway to inhibit SKOV3 cell and HUVEC proliferation, induce apoptosis, suppress migration and metastasis, and inhibit angiogenesis. What's more, Cu-A significantly inhibits ovarian tumor growth in vivo by inhibiting tumor cells from inducing vascular endothelial cells to form their own vasculature and by inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expression of the pro-apoptotic proteins Caspase-9 and Bax to induce apoptosis of tumor cells.
Assuntos
Cobre , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , Apoptose , Movimento Celular , Proliferação de Células , Cobre/farmacologia , Cobre/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The single crystals of two novel chiral tetranucleate copper(II)-based complexes (TNCu-A and TNCu-B) containing L-methioninol-derived Schiff-bases were obtained. Their single structures were characterized by X-ray single crystal diffraction, infrared (IR) rays, elemental analysis, and liquid chromatography-mass spectrometry analysis. TNCu-A can effectively inhibit human umbilical vein endothelial cells (HUVECs) to form a tubular structure and it induces apoptosis of human triple-negative breast cancer MDA-MB-231 cells and HUVECs in vitro in a mitochondria dependent manner. Moreover, in vivo TNCu-A can remarkably inhibit the growth of triple-negative breast cancer from which MDA-MB-231 cells were xenografted into severely immunodeficient nude mice by inhibiting proliferation, inducing apoptosis of MDA-MB-231 cells by dramatically inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expressions of proapoptotic proteins caspase-9 and Bax, and simultaneously inhibiting tumor angiogenesis by decreasing the density of vascular endothelial cells and suppressing migration and even partially inducing apoptosis.
Assuntos
Neoplasias da MamaRESUMO
The single crystals of two novel copper(ii)-based complexes containing l-methioninol-derived Schiff bases were obtained and characterized. The nanoparticles of these complexes were prepared and their cellular uptake was measured in MDA-MB-231 cells and HUVECs. It was found that these complexes could remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis and the growth of triple-negative breast cancer derived from MDA-MB-231 cells in vitro. Meanwhile, these complexes exhibit anticancer and antiangiogenic functions by activating the important protein molecules VEGFR2, FAK, AKT and Erk1/2 or their phosphorylated molecules p-VEGFR2, p-FAK, p-AKT, and p-Erk1/2 in the VEGF/VEGFR2 signaling pathway, collapsing the mitochondrial membrane potential, and damaging the level of reactive oxygen species.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Nanopartículas/química , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Estrutura Molecular , Tamanho da Partícula , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Propriedades de Superfície , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Three novel single crystals of the metal-based complexes Cu-1, Cu-2, and Co-1 were obtained and characterized. Compared with Cu-2 and Co-1, Cu-1 showed remarkable activities of anti-cervical cancer, anti-cisplatin-resistant non-small cell lung cancer and anti-angiogenesis by downregulating the expressions of important proteins in the VEGF/VEGFR2 signaling pathway to inhibit angiogenesis and cancer cell proliferation, induce apoptosis, and suppress migration and metastasis. Moreover, Cu-1 dramatically inhibited the expression of the anti-apoptotic protein Bcl-2 and up-regulated the expressions of the proapoptotic proteins caspase-9 and Bax to induce the apoptosis of tumor cells, simultaneously decreasing the density of endothelial cells to inhibit tumor angiogenesis in cisplatin-resistant tumors.
Assuntos
Antineoplásicos/uso terapêutico , Caspase 9/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína X Associada a bcl-2/metabolismo , Células A549/efeitos dos fármacos , Animais , Apoptose , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Cristalografia por Raios X , Feminino , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Imuno-Histoquímica , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genéticaRESUMO
The single crystals of two novel mixed-ligand copper(ii)-based complexes were obtained and characterized. These complexes can remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis to inhibit the growth of cervical cancer by down-regulating the expressions of the important proteins FAK, Akt and Erk1/2 or their phosphorylated proteins p-FAK, p-Akt, and p-Erk1/2 downstream of the VEGF/VEGFR2 signaling pathway.
Assuntos
Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Complexos de Coordenação/química , Humanos , Ligantes , Modelos Moleculares , Conformação MolecularRESUMO
A novel copper(II) complex with mixed ligands including ß-[(3-formyl-5-methyl-2-hydroxy-benzylidene)amino]propionic acid anion and 1,10'-phenanthroline was synthesized, and its crystal structure was thoroughly characterized. It exerted excellent inducing apoptosis, anti-angiogenesis and antiproliferative properties in vitro. The complex can bind human serum albumin (HSA) at physiological pH conditions. Remarkably, it can induce formation of the mixed parallel/antiparallel G-quadruplex structures in the G-rich sequence of the proximal vascular endothelial growth factor (VEGF) promoter, and stabilize these G-quadruplex structures, which provide an opportunity for anti-angiogenesis chemotherapeutics. Furthermore, the complex showed a strong uptake, and exhibited multiple anticancer functions by inhibiting the expression of p-Akt and p-Erk1/2 proteins and by upregulating the levels of reactive oxygen species (ROS). Because of the reported results, this new copper(II) complex qualifies itself as a potential anticancer drug candidate.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Antineoplásicos/metabolismo , Linhagem Celular , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Quadruplex G , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Conformação Molecular , Fenantrolinas/química , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The crystals of two binuclear copper-based complexes were obtained. One complex can remarkably induce apoptosis and inhibit angiogenesis to mediate tumour growth at a greater extent. Furthermore, this complex showed a strong energy-dependent and non-endocytotic uptake and exhibited multiple anti-cancer functions by inhibiting the expressions of p-Akt and p-Erk1/2 proteins and by decreasing the levels of reactive oxygen species.
Assuntos
Antineoplásicos/farmacologia , Cobre/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
In the title compound, C(6)H(6)Cl(2)N(2)O(2)S, the O atoms of the sulfonamide group lie on one side of the benzene ring and the amino group lies on the opposite side. An inter-molecular N-Hâ¯Cl inter-action occurs. In the crystal, adjacent mol-ecules are linked by N-Hâ¯O hydrogen bonds, forming a three-dimensional structure with supporting π-π stacking inter-actions [centroid-centroid distance = 3.7903â (12)â Å]. A short Clâ¯Cl contact [3.3177â (10)â Å] also occurs.