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1.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668938

RESUMEN

The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 µM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteasas/farmacología , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Relación Estructura-Actividad , Ubiquitina Tiolesterasa/metabolismo
2.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668169

RESUMEN

A series of fifteen silver (I) quinoline complexes Q1-Q15 have been synthesized and studied for their biological activities. Q1-Q15 were synthesized from the reactions of quinolinyl Schiff base derivatives L1-L5 (obtained by condensing 2-quinolinecarboxaldehyde with various aniline derivatives) with AgNO3, AgClO4 and AgCF3SO3. Q1-Q15 were characterized by various spectroscopic techniques and the structures of [Ag(L1)2]NO3Q1, [Ag(L1)2]ClO4Q6, [Ag(L2)2]ClO4Q7, [Ag(L2)2]CF3SO3Q12 and [Ag(L4)2]CF3SO3Q14 were unequivocally determined by single crystal X-ray diffraction analysis. In vitro antimicrobial tests against Gram-positive and Gram-negative bacteria revealed the influence of structure and anion on the complexes' moderate to excellent antibacterial activity. In vitro antioxidant activities of the complexes showed their good radical scavenging activity in ferric reducing antioxidant power (FRAP). Complexes with the fluorine substituent or the thiophene or benzothiazole moieties are more potent with IC50 between 0.95 and 2.22 mg/mL than the standard used, ascorbic acid (2.68 mg/mL). The compounds showed a strong binding affinity with calf thymus-DNA via an intercalation mode and protein through a static quenching mechanism. Cytotoxicity activity was examined against three carcinoma cell lines (HELA, MDA-MB231, and SHSY5Y). [Ag(L2)2]ClO4Q7 with a benzothiazole moiety and [Ag(L4)2]ClO4Q9 with a methyl substituent had excellent cytotoxicity against HELA cells.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Complejos de Coordinación/farmacología , ADN/química , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Férricos/antagonistas & inhibidores , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Quinolinas/química , Quinolinas/farmacología , Bases de Schiff/química , Bases de Schiff/farmacología , Plata/química , Plata/farmacología
3.
Molecules ; 26(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670007

RESUMEN

A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.


Asunto(s)
Antineoplásicos/farmacología , Ácidos Picolínicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/química , Células Tumorales Cultivadas
4.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671733

RESUMEN

The present paper is devoted to the search for drug-like molecules with anticancer properties using the thiazolo[3,2-b][1,2,4]triazole-6-one scaffold. A series of 24 novel thiazolo-[3,2-b][1,2,4]triazole-6-ones with 5-aryl(heteryl)idene- and 5-aminomethylidene-moieties has been synthesized employing three-component and three-stage synthetic protocols. A mixture of Z/E-isomers was obtained in solution for the synthesized 5-aminomethylidene-thiazolo[3,2-b]-[1,2,4]triazole-6-ones. The compounds have been studied for their antitumor activity in the NCI 60 lines screen. Some compounds present excellent anticancer properties at 10 µM. Derivatives 2h and 2i were the most active against cancer cell lines without causing toxicity to normal somatic (HEK293) cells. A preliminary SAR study had been performed for the synthesized compounds.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
5.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671801

RESUMEN

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a-which contains morpholine, aniline, and glycylglycinate methyl ester-showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dipéptidos/farmacología , Triazinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dipéptidos/síntesis química , Dipéptidos/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Triazinas/síntesis química , Triazinas/química , Pez Cebra/embriología
6.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671796

RESUMEN

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient's response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Desarrollo de Medicamentos , Glioma/terapia , Inmunoterapia , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Humanos
7.
Life Sci ; 273: 119305, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33675898

RESUMEN

BACKGROUND: The aim of this study was to synthesize and evaluate anticancer activity of 2-hydroxy benzaldehyde and 4-hydroxy benzaldehyde thiosemicarbazone (2-HBTSc and 4-HBTSc) against MCF-7 breast cancer cell line. MATERIALS AND METHODS: The ligands were prepared and characterized by UV vis, IR and NMR. MTT assay was used to assess viability of cells. RNA isolation, extraction and cDNA synthesis were done. Then all groups were subjected to RT-qPCR using Gene expression specific primers. Also, western blot protein expression and molecular docking were done. Two-way ANOVA with Tukey post-hoc test was employed to test the significance using GraphPad Prism. RESULTS: The IC50 values were 3.36µg/ml and 3.60µg/ml for 2-HBTSc and 4-HBTSc treated MCF-7 tumor cells respectively. Tumor cell growth inhibition ranged from 38 to 49.27% in 4-HBTSc treated cells, and 19 to 25% in 2-HBTSc treated cells with increase in doses 5 µg/ml to 20 µg/ml. The protein and gene expression result showed a significant upregulation in tumor suppressor and apoptosis inducing genes while, oncogene activity was significantly downregulated. Specifically, BRCA2 and pRB gene showed the highest expression in 4-HBTSc and 2-HBTSc treated cells respectively. Conversely, RAS oncogene was downregulated significantly. Docking result showed that both 2-HBTSc and 4-HBTSc have the potential to inhibit Estrogen Receptor Alpha Ligand Binding Domain, Human 17-Beta-hydroxysteroid dehydrogenase type 1 mutant protein and Human Topoisomerase II alpha that are expressed more during Breast Cancer. CONCLUSION: The findings of this study imply that the test compound has potential for further study.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Simulación del Acoplamiento Molecular , Tiosemicarbazonas/química , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Ligandos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad
8.
Eur J Med Chem ; 215: 113267, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33639344

RESUMEN

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.


Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Cetonas/farmacología , Inhibidores de Proteasoma/farmacología , /efectos de los fármacos , Amidas/síntesis química , Amidas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antivirales/síntesis química , Antivirales/metabolismo , Sitios de Unión , Calpaína/química , Calpaína/metabolismo , Línea Celular Tumoral , /metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cetonas/síntesis química , Cetonas/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/metabolismo , Unión Proteica , Relación Estructura-Actividad
9.
ACS Appl Mater Interfaces ; 13(7): 7987-7996, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33560829

RESUMEN

The development of multifunctional photosensitizers (PSs) with aggregation-induced emission (AIE) properties plays a critical role in promoting the progress of the photodynamic therapy (PDT). In this work, a multifunctional PS (named DSABBT NPs) with AIE activity has been designed and prepared to carry out ultrafast staining, excellent two-photon bioimaging, and high-efficiency image-guided PDT. Simply, DSABBT with AIE characteristic was synthesized by one-step Schiff reaction of 4-(diethylamino)-salicylaldehyde (DSA) and 4,7-bis(4-aminophenyl)-2,1,3-benzothiadiazole (BBT). Then, DSABBT and DSPE-PEG2000-cRGD generate nanoparticles (NPs) easily in an ultrapure water/tetrahydrofuran mixture through a facile nanoprecipitation at room temperature. We found that DSABBT NPs exhibit bright solid-state fluorescence with large stokes shifts (180 nm) and two-photon absorption cross-section (1700 GM). Importantly, DSABBT NPs exhibited excellent ability of ultrafast staining and two-photon imaging, which can readily label suborganelles by subtly shaking the living cells for 5 s under mild conditions. Moreover, DSABBT NPs displayed high singlet oxygen (1O2) generation capacity and remarkable image-guided PDT efficiency. Therefore, DSABBT NPs can act as the promising candidate for multifunctional PSs, which can destroy cancer cells and block malignant tumor growth via the production of reactive oxygen species upon irradiation conditions. These outcomes provide us with a selectable strategy for developing multifunctional theranostic systems.


Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Microscopía de Fluorescencia por Excitación Multifotónica , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estructura Molecular , Imagen Óptica , Tamaño de la Partícula , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Propiedades de Superficie
10.
ACS Appl Mater Interfaces ; 13(7): 8940-8951, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33565847

RESUMEN

Chemotherapy is currently the most universal therapeutics to tumor treatment; however, limited curative effect and undesirable drug resistance effect are the two major clinical bottlenecks. Herein, we develop a two-in-one cross-linking strategy to prepare a stimuli-responsive prodrug nanogel by virtue of delivering a combination of chemotherapeutic drugs of 10-hydroxy camptothecin and doxorubicin for ameliorating the deficiencies of chemotherapy and amplifying the cancer therapeutic efficiency. The obtained prodrug nanogel has both high drug loading capacity and suitable nanoscale size, which are beneficial to the cell uptake and tumor penetration. Moreover, the chemotherapeutic drugs are released from the prodrug nanogel in response to the reductive tumor microenvironment, enhancing tumor growth inhibition in vitro and in vivo by the synergistic DNA damage. Based on these results, the unique prodrug nanogel would be a promising candidate for satisfactory tumor treatment-based chemotherapy by a simple but efficient strategy.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Reactivos de Enlaces Cruzados/farmacología , Doxorrubicina/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/química , Cápsulas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , Daño del ADN/efectos de los fármacos , Doxorrubicina/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Nanogeles/química , Oxidación-Reducción , Tamaño de la Partícula , Polietilenglicoles/química , Polietileneimina/química , Profármacos/síntesis química , Profármacos/química , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacos
11.
ACS Appl Mater Interfaces ; 13(5): 6053-6068, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33525873

RESUMEN

Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Citotoxinas/farmacología , Nanomedicina , Compuestos Organoplatinos/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/síntesis química , Camptotecina/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Tamaño de la Partícula , Profármacos/síntesis química , Profármacos/química , Propiedades de Superficie , Células Tumorales Cultivadas
12.
ACS Biomater Sci Eng ; 7(3): 963-982, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33523642

RESUMEN

The rapid rise in research interest in carbohydrate-based polymers is undoubtedly due to the nontoxic nature of such materials in an in vivo environment and the versatile roles that the polymers can play in cellular functions. Such polymers have served as therapeutic tools for drug delivery, including antigens, proteins, and genes, as well as diagnostic devices. Our focus in the first half of this Review is on synthetic methods based on ring-opening polymerization and enzyme-catalyzed polymerization, along with controlled radical polymerization. In the second half of this Review, sugar-based polymers are discussed on the basis of their remarkable success in competitive receptor binding, as multifunctional nanocarriers of targeting inhibitors for cancer treatment, in genome-editing delivery, in immunotherapy based on endogenous antibody recruitment, and in treatment of respiratory diseases, including influenza A. Particular emphasis is put on the synthesis and biopharmaceutical applications of sugar-based polymers published in the most recent 5 years. A noticeable attribute of carbohydrate-based polymers is that the sugar-receptor interactions can be facilitated by the cooperative effect of multiple sugar units. Their diversified topology and structures will drive the development of new synthetic strategies and bring about important applications, including coronavirus-related drug therapy.


Asunto(s)
Glicósidos/síntesis química , Glicósidos/uso terapéutico , Polímeros/síntesis química , Polímeros/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/uso terapéutico , Línea Celular Tumoral , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/uso terapéutico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Técnicas de Transferencia de Gen , Glicósidos/metabolismo , Humanos , Virus de la Influenza A/efectos de los fármacos , Lectinas/metabolismo , Nanopartículas/química , Nanopartículas/uso terapéutico , Polímeros/metabolismo
13.
Molecules ; 26(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546225

RESUMEN

Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound 2e displayed the most excellent activity with an IC50 value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound 2e. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound 2e or compound 2e combined with cyclophosphamide (CTX) (p < 0.05, p < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound 2e caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound 2e was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound 2e is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.


Asunto(s)
Aminoácidos/química , Antineoplásicos , Carcinoma Hepatocelular/tratamiento farmacológico , Ginsenósidos/química , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Molecules ; 26(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546294

RESUMEN

Coumarins possesses immeasurable antitumor potential with minimum side effects depending on the substitutions on the basic nucleus, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, a series of coumarin sulfonamides and amides derivatives were designed and synthetized. The majority of these derivatives showed good cytotoxic activity against MDA-MB-231 and KB cell lines, among which compound 9c was the most potent against MDA-MB-231 cells, with IC50 value of 9.33 µM, comparable to 5-fluorouracil. Further investigation revealed that compound 9c had versatile properties against tumors, including inhibition of cell migration and invasion as well as inducing apoptosis. Reactive oxygen species (ROS) assay and western blotting analysis suggested that compound 9c promoted cancer cell apoptosis by increasing ROS levels and upregulating the expression of caspase-3 in MDA-MB-231 cells. These results indicated that compound 9c could be promising lead compound for further antitumor drug research.


Asunto(s)
Cumarinas , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Sulfonamidas , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/farmacología , Células HCT116 , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología
15.
J Med Chem ; 64(3): 1584-1592, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33522809

RESUMEN

Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 µM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Simulación por Computador , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , N-Metiltransferasa de Histona-Lisina/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Dominios Proteicos , Proteínas Represoras/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
16.
J Med Chem ; 64(3): 1701-1712, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529017

RESUMEN

Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Fase G2/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-Dawley , Solubilidad , Ensayos Antitumor por Modelo de Xenoinjerto
17.
J Med Chem ; 64(3): 1524-1544, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529023

RESUMEN

Clinical and preclinical data reveal that RECQL5 protein overexpression in breast cancer was strongly correlated with poor prognosis, survival, and therapeutic resistance. In the current investigation, we report design, synthesis, and specificity of a small molecule, 4a, which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 4a specifically sensitizes RECQL5-expressing cancers, while it did not have any effect on other members of DNA RECQL-helicases. Integrated approaches of organic synthesis, biochemical, in silico molecular simulation, knockouts, functional mutation, and rescue experiments showed that 4a potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, 4a treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 4a was orally effective in reducing the growth of RECQL5-expressing breast tumors (human xenograft) in NUDE-mice with no appreciable toxicity to the vital organs.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , RecQ Helicasas/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/toxicidad , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Simulación por Computador , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Modelos Moleculares , RecQ Helicasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
18.
J Med Chem ; 64(3): 1725-1732, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529029

RESUMEN

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Profármacos/síntesis química , Profármacos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Ratones , Modelos Moleculares , Profármacos/farmacocinética , Piridonas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Molecules ; 26(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33573040

RESUMEN

In an effort to improve and achieve biologically active anticancer agents, a novel series of 1,2,3-triazole-containing hybrids were designed and efficiently synthesized via the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of substituted-arylazides with alkyne-functionalized pyrazole-[1,2,4]-triazole hybrids. The structure geometry of these new clicked 1,2,3-triazoles was explored by density functional theory (DFT) using the B3LYP/6-311++G(d,p) level; also, the potential activity of the compounds for light absorption was simulated by time-dependent DFT calculations (TD-DFT). The antitumor impacts of the newly synthesized compounds were in vitro estimated to be towards the human liver cancer cell line (HepG-2), the human colon cancer cell line (HCT-116), and human breast adenocarcinoma (MCF-7). Among the tested compounds, conjugate 7 was the most potent cytotoxic candidate towards HepG-2, HCT-116, and MCF-7, with IC50 = 12.22, 14.16, and 14.64 µM, respectively, in comparison to that exhibited by the standard drug doxorubicin (IC50 = 11.21, 12.46, and 13.45 µM). Finally, a molecular docking study was conducted within the epidermal growth factor receptor (EGFR) active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that analogies 7, 6, and 5 could be considered as decent lead candidate compounds for anticancer agents.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Triazoles/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Química Clic , Reacción de Cicloadición , Teoría Funcional de la Densidad , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacología
20.
Food Chem ; 342: 128378, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33508903

RESUMEN

Rheum ribes L. (Rhubarb) is one of the most important edible medicinal plants in the Eastern Anatolia region and is called "Iskin" by local people. Resveratrol and 6-O-methylalaternin were isolated from the Rhubarb for the first time in addition to well-known secondary metabolites including emodin, aloe-emodin, ß-sitosterol and rutin. The new semi-synthetic anthraquinone derivatives with the NαFmoc-l-Lys and ethynyl group were synthesized from the isolated anthraquinones emodin and aloe-emodin of Rhubarb to increase the bioactivities. Aloe-emodin derivative with NαFmoc-l-Lys shows the highest inhibition values by 94.11 ± 0.12 and 82.38 ± 0.00% against HT-29 and HeLa cell lines, respectively, at 25 µg/mL. Further, modification of the aloe-emodin with both the ethynyl and the NαFmoc-l-Lys groups showed an antioxidant activity-enhancing effect. From molecular docking studies, the relative binding energies of the emodin and aloe-emodin derivatives to human serum albumin ranged from -7.30 and -10.62 kcal/mol.


Asunto(s)
Antraquinonas/química , Antineoplásicos/síntesis química , Resveratrol/química , Rheum/química , Antraquinonas/síntesis química , Antraquinonas/aislamiento & purificación , Antraquinonas/metabolismo , Antraquinonas/farmacología , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Emodina/química , Emodina/aislamiento & purificación , Emodina/metabolismo , Emodina/farmacología , Humanos , Simulación del Acoplamiento Molecular , Componentes Aéreos de las Plantas/química , Componentes Aéreos de las Plantas/metabolismo , Resveratrol/aislamiento & purificación , Resveratrol/farmacología , Rheum/metabolismo , Albúmina Sérica/química , Albúmina Sérica/metabolismo
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