RESUMEN
The introduction of combined antiretroviral therapy (cART) has greatly improved the quality of life of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, the ever-present desire to seek out a full remedy for HIV-1 infections makes the discovery of novel antiviral medication compelling. Owing to this, a new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting late-stage proteins or processes, newer therapeutics targeting host restriction factors hold promise for the curative care of HIV-1 infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is an appealing HIV-1 therapeutic candidate. In this study, a novel drug screening system was established, using the Jurkat/Vpr-HiBiT T cells, to identify drugs that could obstruct HIV-1 release; the candidate compounds were selected from the Ono Pharmaceutical compound library. Jurkat T cells expressing Vpr-HiBiT were infected with NL4-3, and the amount of virus release was quantified indirectly by the amount of Vpr-HiBiT incorporated into the progeny virions. Subsequently, the candidate compounds that suppressed viral release were used to synthesize the heterocyclic compound, HT-7, which reduces HIV-1 release with less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled with HIV-1 release reduction in Jurkat cells but not Jurkat/KO-BST2 cells. Seemingly, HT-7 impeded simian immunodeficiency virus (SIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) release. Concisely, these results suggest that the reduction in viral release, following HT-7 treatment, resulted from the modulation of cell surface expression of BST2 by HT-7.
RESUMEN
AMPK activation promotes glucose and lipid metabolism. Here, we found that our previously reported ADAM17 inhibitor SN-4 activates AMPK and promotes membrane translocation and sugar uptake of GLUT4. AMPK inhibitor dorsomorphin reversed this effect of SN-4, confirming that the effect is mediated by AMPK activation. In addition, SN-4 inhibited lipid accumulation in HepG2 under high glucose conditions by promoting lipid metabolism and inhibiting lipid synthesis. Although lactic acidosis is a serious side effect of biguanides such as metformin, SN-4 did not affect lactate production. Furthermore, SN-4 was confirmed to inhibit the release of TNF-α, a causative agent of insulin resistance, from adipocytes. In diabetes treatment, it is important to not only regulate blood sugar levels but also prevent complications. Our findings reveal the therapeutic potential of SN-4 as a new antidiabetic drug that can also help prevent future complications.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Metformina , Proteínas Quinasas Activadas por AMP/metabolismo , Hipoglucemiantes/farmacología , Glucosa/metabolismo , Metformina/farmacología , Lípidos , Transportador de Glucosa de Tipo 4RESUMEN
Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body's health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients' bodies. A potential strategy called "lock-in and apoptosis" targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , VIH-1 , Estados Unidos , Humanos , United States Food and Drug Administration , Apoptosis , División CelularRESUMEN
Infection with the retrovirus human T-cell leukemia virus type 1 (HTLV-1) sometimes causes diseases that are difficult to cure. To find anti-HTLV-1 natural compounds, we opted to screen using the HTLV-1-infected T-cell line, MT-2. Based on our results, an extract of the pulp/seeds of Akebia quinata Decaisne fruit killed MT-2 cells but did not affect the Jurkat cell line that was not infected with virus. To determine the active ingredients, seven saponins with one-six sugar moieties were isolated from A. quinata seeds, and their activities against the two cell lines were examined. Both cell lines were killed in a similar manner by Akebia saponins A and B. Further, Akebia saponins D, E, PK and G did not exhibit cytotoxicity. Akebia saponin C had a similar activity to the extract found in the screening. This compound was found to enhance Gag aggregation, induce the abnormal cleavage of Gag, suppress virion release, and preferentially kill HTLV-1 infected cells; however, their relationship remains elusive. Our findings may lead to the development of new therapies for infectious diseases based on the removal of whole-virus-infected cells.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Saponinas , Humanos , Línea Celular , Saponinas/farmacología , Células Jurkat , Extractos VegetalesRESUMEN
Drug repurposing is a distinguished approach for drug development that saves a great deal of time and money. Based on our previous successful repurposing of a compound BMMP from anti-HIV-1 therapy to anti-cancer metastatic activity, we adopted the same techniques for repurposing benzimidazole derivatives considering MM-1 as a lead compound. An extensive structure-activity relationship (SAR) study afforded three promising compounds, MM-1d, MM-1h, and MM-1j, which inhibited cell migration in a similar fashion to BMMP. These compounds suppressed CD44 mRNA expression, whereas only MM-1h further suppressed mRNA expression of the epithelial-mesenchymal transition (EMT) marker zeb 1. Using benzimidazole instead of methyl pyrimidine as in BMMP resulted in better affinity for heterogeneous nuclear ribonucleoprotein (hnRNP) M protein and higher anti-cell migration activity. In conclusion, our study identified new agents that surpass the affinity of BMMP for hnRNP M and have anti-EMT activity, which makes them worthy of future attention and optimization.
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Reposicionamiento de Medicamentos , Ribonucleoproteína Heterogénea-Nuclear Grupo M , Línea Celular Tumoral , Inhibición de Migración Celular , ARN Mensajero/genéticaRESUMEN
The introduction of combined anti-retroviral therapy (cART) in 1996, along with a continual breakthrough in anti-human immunodeficiency virus-1 (HIV-1) drugs, has improved the life expectancies of HIV-1-infected individuals. However, the incidence of drug-resistant viruses between individuals undergoing cART and treatment-naïve individuals is a common challenge. Therefore, there is a requirement to explore potential drug targets by considering various stages of the viral life cycle. For instance, the late stage, or viral release stage, remains uninvestigated extensively in antiviral drug discovery. In this study, we prepared a natural plant library and selected candidate plant extracts that inhibited HIV-1 release based on our laboratory-established screening system. The plant extracts from Epilobium hirsutum L. and Chamerion angustifolium (L.) Holub, belonging to the family Onagraceae, decreased HIV-1 release and accelerated the apoptosis in HIV-1-infected T cells but not uninfected T cells. A flavonol glycoside quercetin with oenothein B in Onagraceae reduced HIV-1 release in HIV-1-infected T cells. Moreover, extracts from Chamerion angustifolium (L.) Holub and Senna alexandrina Mill. inhibited the infectivity of progeny viruses. Together, these results suggest that C. angustifolium (L.) Holub contains quercetin with oenothein B that synergistically blocks viral replication and kills infected cells via an apoptotic pathway. Consequently, the plant extracts from the plant library of Turkey might be suitable candidates for developing novel anti-retroviral drugs that target the late phase of the HIV-1 life cycle.
Asunto(s)
VIH-1 , Onagraceae , Humanos , Quercetina/farmacología , Extractos Vegetales/farmacología , Turquía , ApoptosisRESUMEN
We designed and synthesized a chiral ligand N-(anthracen-9-ylmethyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)ethanamine (APPE) DNA photocleavage agent to investigate the effects of chirality of bis(2-picolyl)amine on the DNA photocleavage activity of metal complexes. The structures of ZnII and CoII complexes in APPE were analyzed via X-ray crystallography and fluorometric titration. APPE formed metal complexes with a 1 : 1 stoichiometry in both the crystalline and solution states. Fluorometric titration was used to show that the ZnII and CoII association constants of these complexes (log Kas) were 4.95 and 5.39, respectively. The synthesized complexes were found to cleave pUC19 plasmid DNA when irradiated at 370 nm. The DNA photocleavage activity of the ZnII complex was higher than that of the CoII complex. The absolute configuration of the methyl-attached carbon did not affect DNA cleavage activity and, unfortunately, an achiral APPE derivative without the methyl group (ABPM) was found to perform DNA photocleavage more effectively than APPE. One reason for this may be that the methyl group suppressed the structural flexibility of the photosensitizer. These results will be useful for the design of new photoreactive reagents.
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Complejos de Coordinación , Zinc , Zinc/química , Cobalto/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Cobre/química , Aminas/química , ADN/química , Cristalografía por Rayos X , LigandosRESUMEN
In the last decade, gypsogenin has attracted widespread attention from medicinal chemists by virtue of its prominent anti-cancer potential. Despite its late identification, gypsogenin has proved itself as a new anti-proliferative player battling for a frontline position among other classic pentacyclic triterpenes such as oleanolic acid, glycyrrhetinic acid, ursolic acid, betulinic acid, and celastrol. Herein, we present the most important reactions of gypsogenin via modification of its four functional groups. Furthermore, we demonstrate insights into the anti-cancer activity of gypsogenin and its semisynthetic derivatives and go further by introducing our perspective to judiciously guide the prospective rational design. The present article opens a new venue for a better exploitation of gypsogenin chemical entity as a lead compound in cancer chemotherapy. To the best of our knowledge, this is the first review article exploring the anti-cancer activity of gypsogenin derivatives.
Asunto(s)
Neoplasias , Ácido Oleanólico , Saponinas , Triterpenos , Humanos , Estudios Prospectivos , Triterpenos Pentacíclicos/química , Triterpenos/química , Saponinas/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
1,2-Naphthoquinone (2-NQ) is a nucleophile acceptor that non-selectively makes covalent bonds with cysteine residues in various cellular proteins, and is also found in diesel exhaust, an air pollutant. This molecule has rarely been considered as a pharmacophore of bioactive compounds, in contrast to 1,4-naphthoquinone. We herein designed and synthesized a compound named N-(7,8-dioxo-7,8-dihydronaphthalen-1-yl)-2-methoxybenzamide (MBNQ), in which 2-NQ was hybridized with the nuclear factor-κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) as a nucleophile acceptor. Although 50 µM MBNQ did not inhibit NF-κB signaling, 10 µM MBNQ induced cell death in the lung cancer cell line A549, which was insensitive to 2-NQ (10 µM). In contrast, MBNQ was less toxic in normal lung cells than 2-NQ. A mechanistic study showed that MBNQ mainly induced apoptosis, presumably via the activation of p38 mitogen-activated protein kinase (MAPK). Collectively, the present results demonstrate that the introduction of an appropriate substituent into 2-NQ constitutes a new biologically active entity, which will lead to the development of 2-NQ-based drugs.
Asunto(s)
Neoplasias Pulmonares , Naftoquinonas , Apoptosis , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , FN-kappa B/metabolismo , Naftoquinonas/farmacologíaRESUMEN
Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-ß (TGF-ß). Although several classes of inhibitors targeting TGF-ß and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-ß Smad-dependent signaling. In this study, 10 µM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-ß signaling. This downstream inhibition blocks the expression of cytokines such as TGF-ß, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action.
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Carcinoma de Pulmón de Células no Pequeñas , Transición Epitelial-Mesenquimal , Transducción de Señal , Factor de Crecimiento Transformador beta , Proteínas Quinasas Activadas por AMP , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Crecimiento TransformadoresRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Terapia Combinada/métodos , Estimulación Encefálica Profunda , Descubrimiento de Drogas , Edaravona/uso terapéutico , Humanos , Células Madre Pluripotentes Inducidas/trasplante , Riluzol/uso terapéuticoRESUMEN
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Simulación por Computador , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/farmacología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/química , Pirazoles/farmacocinéticaRESUMEN
Colorectal cancer (CRC), breast cancer, and chronic myeloid leukemia (CML) are life-threatening malignancies worldwide. Although potent therapeutic and screening strategies have been developed so far, these cancer types are still major public health problems. Therefore, the exploration of more potent and selective new agents is urgently required for the treatment of these cancers. Quinones represent one of the most important structures in anticancer drug discovery. We have previously identified a series of quinone-based compounds (ABQ-1-17) as anti-CML agents. In the current work, ABQ-3 was taken to the National Cancer Institute (NCI) for screening to determine its in vitro antiproliferative effects against a large panel of human tumor cell lines at five doses. ABQ-3 revealed significant growth inhibition against HCT-116 CRC and MCF-7 breast cancer cells with 2.00 µM and 2.35 µM GI50 values, respectively. The MTT test also showed that ABQ-3 possessed anticancer effects towards HCT-116 and MCF-7 cells with IC50 values of 5.22 ± 2.41 µM and 7.46 ± 2.76 µM, respectively. Further experiments indicated that ABQ-3 induced apoptosis in both cell lines, and molecular docking studies explicitly suggested that ABQ-3 exhibited DNA binding in a similar fashion to previously reported compounds. Based on in silico pharmacokinetic prediction, ABQ-3 might display drug-like features enabling this compound to become a lead molecule for future studies.
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Antineoplásicos , Neoplasias , Humanos , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Línea Celular Tumoral , Quinonas/farmacología , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 µM compared to cisplatin (IC50 = 26.65 ± 7.85 µM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Plastoquinona/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Simulación por Computador , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Plastoquinona/metabolismo , Relación Estructura-ActividadRESUMEN
DNA-cleavage agents such as bleomycin have potential anticancer applications. The development of a DNA-cleavage reagent that recognizes specific sequences allows the development of cancer therapy with reduced side effects. In this study, to develop novel compounds with specific DNA-cleavage activities, we synthesized optically active binuclear ligands, (1R,1'R,2R,2'R)-N1,N1'-(meta/para-phenylenebis(methylene))bis(N2,N2-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine) and their enantiomers. The DNA-cleavage activities of these compounds were investigated in the presence of Fe(II)SO4 and sodium ascorbate. The obtained results indicated that the Fe(II) complexes of those compounds efficiently cleave DNA and that their cleavage was subtle sequence-selective. Therefore, we succeeded in developing compounds that can be used as small-molecule drugs for cancer chemotherapy.
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Ciclohexilaminas/farmacología , Compuestos Ferrosos/farmacología , Ciclohexilaminas/síntesis química , Ciclohexilaminas/química , División del ADN , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Ligandos , Estructura Molecular , Plásmidos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
It is necessary to design a ligand that is compatible with the target molecule to optimally use the DNA-cleaving ability of metal complexes. In this study, we synthesized an optically active dinuclear ligand, (1R,1'R,2R,2'R)-N1,N1'-(anthracene-1,8-diylbis(methylene))bis(N2,N2-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine) (R-ABDC, 4a) and its enantiomer (S-ABDC, 4b). We then prepared their Fe(II) complexes by mixing the ligand with FeSO4·7H2O in situ and investigated DNA-cleaving activities using plasmid DNA in the presence of excess sodium ascorbate at atmospheric conditions. The Fe(II) complexes efficiently cleaved DNA and selectively recognized two consecutive A and/or T sequences.
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ADN/efectos de los fármacos , Diseño de Fármacos , Compuestos Ferrosos/farmacología , División del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Ligandos , Estructura Molecular , Plásmidos , Relación Estructura-ActividadRESUMEN
Literature conclusively shows that one of the quinolinequinone analogs (6-anilino-5,8-quinolinequinone), referred to as LY83583 hereafter, an inhibitor of guanylyl cyclase, was used as the inhibitor of the cell proliferation in cancer cells. In the present work, a series of analogs of the LY83583 containing alkoxy group(s) in aminophenyl ring (AQQ1-15) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against four different cancer cell lines (K562, Jurkat, MT-2, and HeLa) and human peripheral blood mononuclear cells (PBMCs) by MTT assay. The analog (AQQ13) was identified to possess the most potent cytotoxic activity against K562 human chronic myelogenous (CML) cell line (IC50 = 0.59 ± 0.07 µM) with significant selectivity (SI = 4.51) compared to imatinib (IC50 = 5.46 ± 0.85 µM; SI = 4.60). Based on its superior cytotoxic activity, the analog AQQ13 was selected for further mechanistic studies including determination of its apoptotic effects on K562 cell line via annexin V/ethidium homodimer III staining potency, ABL1 kinase inhibitory activity, and DNA cleaving capacity. Results ascertained that the analog AQQ13 induced apoptosis in K562 cell line with notable DNA-cleaving activity. However, AQQ13 demonstrated weak ABL1 inhibition indicating the correlation between anti-K562 and anti-ABL1 activities. In continuance, respectively conducted in silico molecular docking and Absorption, Distribution, Metabolism, and Excretion (ADME) studies drew attention to enhanced binding interactions of AQQ13 towards DNA and its high compatibility with the potential limits of specified pharmacokinetic parameters making it as a potential anti-leukemic drug candidate. Our findings may provide a new insight for further development of novel quinolinequinone-based anticancer analogs against CML.
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Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , División del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/metabolismo , Relación Estructura-ActividadRESUMEN
One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-ß (TGF-ß). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.
Asunto(s)
Fármacos Anti-VIH/química , Compuestos Heterocíclicos/química , Ribonucleoproteína Heterogénea-Nuclear Grupo M/metabolismo , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Línea Celular , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/metabolismo , Compuestos Heterocíclicos/farmacología , Ribonucleoproteína Heterogénea-Nuclear Grupo M/antagonistas & inhibidores , Ribonucleoproteína Heterogénea-Nuclear Grupo M/genética , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Unión Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/química , ARN Interferente Pequeño/metabolismoRESUMEN
New quinoline / chalcone hybrids containing 1,2,4-triazole moiety have been designed, synthesized and their structures elucidated and confirmed by various spectroscopic techniques. The designed compounds showed moderate to good activity on different NCI 60 cell lines in a single-dose assay with a growth inhibition rate ranging from 50% to 94%. Compounds 7b, 7d, 9b, and 9d were the most active compounds in most cancer cell lines with a growth inhibition percent between 77% and 94%. Newly synthesized hybrids were evaluated for their anti-proliferative activity against a panel of four human cancer cell lines. Compounds 7a, 7b, 9a, 9b, and 9d showed promising antiproliferative activities. These compounds were further tested for their inhibitory potency against EGFR and BRAFV600E kinases with erlotinib as a reference drug. The molecular docking study of compounds 7a, 7b, 9a, 9b, and 9d revealed nice fitting into the active site of EGFR and BRAFV600E kinases. Compounds 7b, 9b, and 9d displayed the highest binding affinities and similar binding pattern to those of erlotinib.
Asunto(s)
Antineoplásicos/farmacología , Chalcona/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Quinolinas/farmacología , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Chalcona/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Quinolinas/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
A disintegrin and metalloproteinase 17 (ADAM17) is a zinc-dependent enzyme that catalyzes the cleavage of the extracellular domains of various transmembrane proteins. ADAM17 is regarded as a promising drug target for the suppression of various diseases, including cancer metastasis. We synthesized a new ADAM17 inhibitor, SN-4, composed of a zinc-binding dithiol moiety and an appendage that specifically binds to a pocket of ADAM17. We show that SN-4 inhibits the ability of ADAM17 to cleave tumor necrosis factor α (TNF-α) in vitro. This activity was reduced by the addition of zinc, indicating the importance of the zinc chelating dithiol moiety. Inhibition of TNF-α cleavage by SN-4 in cells was also observed, and with an IC50 of 3.22 µM, SN-4 showed slightly higher activity than the well-studied ADAM17 inhibitor marimastat. Furthermore, SN-4 was shown to inhibit cleavage of CD44 by ADAM17, but not by ADAM10, and to suppress cell invasion. Molecular docking showed good fitting of the specificity pocket-binding group and one SH of SN-4 and hinted at possible means of structural optimization. This study provides clues for the development of potent and selective ADAM17 inhibitors.