RESUMEN
Multi-walled Carbon Nanotubes (MWCNTs) are inert structures with high aspect ratios that are widely used as vehicles for targeted drug delivery in cancer and many other diseases. They are largely non-toxic in nature however, when cells are exposed to these nanotubes for prolonged durations or at high concentrations, they show certain adverse effects. These include cytotoxicity, inflammation, generation of oxidative stress, and genotoxicity among others. To combat such adverse effects, various moieties can be attached to the surface of these nanotubes. Curcumin is a known anti-inflammatory, antioxidant and cytoprotective compound derived from a medicinal plant called Curcuma longa. In this study, we have synthesized and characterized Curcumin coated-lysine functionalized MWCNTs and further evaluated the cytoprotective, anti-inflammatory, antioxidant and antiapoptotic effect of Curcumin coating on the surface of MWCNTs. The results show a significant decrease in the level of inflammatory molecules like IL-6, IL-8, IL-1ß, TNFα and NFκB in cells exposed to Curcumin-coated MWCNTs as compared to the uncoated ones at both transcript and protein levels. Further, compared to the uncoated samples, there is a reduction in ROS production and upregulation of antioxidant enzyme-Catalase in the cells treated with Curcumin-coated MWCNTs. Curcumin coating also helped in recovery of mitochondrial membrane potential in the cells exposed to MWCNTs. Lastly, cells exposed to Curcumin-coated MWCNTs showed reduced cell death as compared to the ones exposed to uncoated MWCNTs. Our findings suggest that coating of Curcumin on the surface of MWCNTs reduces its ability to cause inflammation, oxidative stress, and cell death.
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Curcumina , Nanotubos de Carbono , Humanos , Curcumina/farmacología , Nanotubos de Carbono/toxicidad , Nanotubos de Carbono/química , Antioxidantes/farmacología , Inflamación , Antiinflamatorios/farmacologíaRESUMEN
Multiple malignancies exhibit aberrant FASN expression, associated with enhanced de novo lipogenesis to meet the metabolic demands of rapidly proliferating tumour cells. Furthermore, elevated FASN expression has been linked to tumour aggressiveness and poor prognosis in a variety of malignant tumours, making FASN is an attractive target for anticancer drug discovery. Herein, we report the de novo design and synthesis of (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives as novel FASN inhibitors with potential therapeutic applications in breast and colorectal cancers. Twelve (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives (CTL) were synthesized and evaluated for FASN inhibition and cytotoxicity against colon cancer (HCT-116, Caco-2 cell lines), breast cancer (MCF-7 cell line) and normal cell line (HEK-293). Compounds CTL-06 and CTL-12 were chosen as the most promising lead molecules based on FASN inhibition and selective cytotoxicity profiles against colon and breast cancer cell lines. Compounds CTL-06 and CTL-12 demonstrate promising FASN inhibitory activity at IC50 of 3 ± 0.25 µM and 2.5 ± 0.25 µM when compared to the FASN inhibitor orlistat, which has an IC50 of 13.5 ± 1.0 µM. Mechanistic investigations on HCT-116 revealed that CTL-06 and CTL-12 treatment led to cell cycle arrest in Sub-G1/S phase along with apoptosis induction. Western blot studies indicated that CTL-06 and CTL-12 inhibited FASN expression in a dose-dependent manner. CTL-06 and CTL-12 treatment of HCT-116 cells enhanced caspase-9 expression in a dose-dependent manner, while upregulating proapoptotic marker Bax and downregulating antiapoptotic Bcl-xL. Molecular docking experiments of CTL-06 and CTL-12 with FASN enzyme revealed the mode of binding of these analogues in the KR domain of the enzyme.
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Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Simulación del Acoplamiento Molecular , Células CACO-2 , Células HEK293 , Ácido Graso Sintasas/química , Ácido Graso Sintasas/metabolismo , Imidazoles/farmacología , Línea Celular Tumoral , Apoptosis , Antineoplásicos/químicaRESUMEN
Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug-loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin-loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.
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Antineoplásicos , Neoplasias de la Mama , Nanotubos de Carbono , Humanos , Femenino , Nanotubos de Carbono/química , Ligandos , Espectroscopía Infrarroja por Transformada de Fourier , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Microambiente TumoralRESUMEN
A novel series of 4-anilinoquinazoline analogues, DW (1-10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.
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Apoptosis/efectos de los fármacos , Neoplasias del Colon , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células HCT116 , Células HT29 , HumanosRESUMEN
A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC50 of 1.88⯵M against reference standard suramin (IC50â¯≥â¯10⯵M). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.
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Acetamidas/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Tetrazoles/farmacología , Acetamidas/síntesis química , Acetamidas/química , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Estreptozocina , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/químicaRESUMEN
A series of lH-pyrazolo[3,4-b]quinolin-3-amine derivatives were synthesized and evaluated for anticancer efficacy in a panel of ten cancer cell lines, including breast (MDAMB-231 and MCF-7), colon (HCT-116, HCT-15, HT-29 and LOVO), prostate (DU-145 and PC3), brain (LN-229), ovarian (A2780), and human embryonic kidney (HEK293) cells, a non-cancerous cell line. Among the eight derivatives screened, compound QTZ05 had the most potent and selective antitumor efficacy in the four colon cancer cell lines, with IC50 values ranging from 2.3 to 10.2⯵M. Furthermore, QTZ05 inhibited colony formation in HCT-116 cells in a concentration-dependent manner. Cell cycle analysis data indicated that QTZ05 caused an arrest in the sub G1 cell cycle in HCT-116 cells. QTZ05 induced apoptosis in HCT-116 cells in a concentration-dependent manner that was characterized by chromatin condensation and increase in the fluorescence of fluorochrome-conjugated Annexin V. The findings from our study suggest that QTZ05 may be a valuable prototype for the development of chemotherapeutics targeting apoptotic pathways in colorectal cancer cells.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Pirazoles/farmacología , Quinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Células HEK293 , Humanos , Pirazoles/síntesis química , Pirazoles/toxicidad , Quinolinas/síntesis química , Quinolinas/toxicidadRESUMEN
Described herein is the synthesis and biological evaluation of a series of non-carboxylic inhibitors of Protein Tyrosine Phosphatase 1B designed using bioisosteric replacement strategy. Six N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed employing the aforementioned strategy were synthesized and screened for PTP1B inhibitory activity. Among the synthesized compounds, compound NM-03 exhibited the most potent inhibitory activity with IC50 value of 4.48⯵M. Docking studies with NM-03 revealed the key interactions with desired amino acids in the binding site of PTP1B. Furthermore, compound NM-03 also elicited good in vivo activity. Taken together, the results of this study establish N-(3-(1H-tetrazole-5-yl)phenyl)-2-(benzo[d]oxazol-2-ylthio)acetamide (NM-03) as a valuable lead molecule with great potential for PTP1B inhibitor development targeting diabetes.
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Acetamidas/química , Inhibidores Enzimáticos/síntesis química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Acetamidas/metabolismo , Acetamidas/uso terapéutico , Animales , Sitios de Unión , Glucemia/análisis , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Prueba de Tolerancia a la Glucosa , Humanos , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Ratas , Relación Estructura-Actividad , Tetrazoles/químicaRESUMEN
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/ß, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.
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Caseína Cinasa 1 épsilon/antagonistas & inhibidores , Quinasa Idelta de la Caseína/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Quinazolinas/farmacología , Caseína Cinasa 1 épsilon/metabolismo , Quinasa Idelta de la Caseína/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
Lymphoma is the most common hematopoietic tumor in dogs and humans, with similar pathogenesis and therapeutic responses. Anticancer drugs like vincristine (VCR) and doxorubicin (DOX) are often used in treating lymphoma. However, the cure rate is generally poor due to chemoresistance. Here, we sought to determine whether stearidonic acid (SDA), a plant-based dietary fatty acid, sensitizes chemoresistant canine lymphoid-tumor cells. GL-1 B-cell lymphoid-tumor cells were found to be highly sensitive to the antitumor-activity of VCR and DOX, while OSW T-cell and 17-71 B-cell lymphoid-tumor cells were moderately and fully resistant, respectively. SDA, at its non-toxic concentrations, significantly promoted the antitumor action of VCR and DOX in both OSW and 17-71 cells. SDA-mediated chemosensitization was associated with SDA inhibition of P-glycoprotein (P-gp) function. This was confirmed in HEK293 cells stably expressing P-gp as well as by increased binding-affinity of SDA to P-gp in P-gp docking analysis. SDA at its chemosensitizing concentrations did not affect the viability of healthy dog peripheral blood mononuclear cells, suggesting that SDA is non-toxic to normal dog peripheral blood leucocytes at its chemosensitizing concentrations. Our study identifies a novel dietary fatty acid that may be used as a dietary supplement in combination with chemotherapy to promote the antitumor efficacy of the chemotherapy drugs in dogs and possibly in humans with chemoresistant lymphoma.
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Antineoplásicos/uso terapéutico , Ácidos Grasos Omega-3/farmacología , Linfoma de Células B/tratamiento farmacológico , Plantas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular Tumoral , Perros , Sinergismo Farmacológico , Ácidos Grasos Omega-3/uso terapéuticoRESUMEN
Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1â³,2â³:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1â³,2â³:1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.
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Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Quinolinas/farmacología , Animales , Antineoplásicos/farmacología , Perros , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HEK293 , Células Hep G2 , Humanos , Células MCF-7 , Células de Riñón Canino Madin Darby , Ratones , Pirimidinas/farmacologíaRESUMEN
A series of novel 4-anilinoquinazoline derivatives (3a-3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimer's disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3α/ß kinase with IC50 values of 1.5 µM and 3 µM, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3ß. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3α/ß enzymes with potential therapeutic application in Alzheimer's disease.
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Compuestos de Anilina/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
Multiwalled carbon nanotubes (MWCNTs) are at the forefront of nanotechnology-based advancements in cancer therapy, particularly in the field of targeted drug delivery. The nanotubes are characterized by their concentric graphene layers, which give them outstanding structural strength. They can deliver substantial doses of therapeutic agents, potentially reducing treatment frequency and improving patient compliance. MWCNTs' diminutive size and modifiable surface enable them to have a high drug loading capacity and penetrate biological barriers. As a result of the extensive research on these nanomaterials, they have been studied extensively as synthetic and chemically functionalized molecules, which can be combined with various ligands (such as folic acid, antibodies, peptides, mannose, galactose, polymers) and linkers, and to deliver anticancer drugs, including but not limited to paclitaxel, docetaxel, cisplatin, doxorubicin, tamoxifen, methotrexate, quercetin and others, to cancer cells. This functionalization facilitates selective targeting of cancer cells, as these ligands bind to specific receptors overexpressed in tumor cells. By sparing non-cancerous cells and delivering the therapeutic payload precisely to cancer cells, this therapeutic payload delivery ability reduces chemotherapy systemic toxicity. There is great potential for MWCNTs to be used as targeted delivery systems for drugs. In this review, we discuss techniques for functionalizing and conjugating MWCNTs to drugs using natural and biomacromolecular linkers, which can bind to the cancer cells' receptors/biomolecules. Using MWCNTs to administer cancer drugs is a transformative approach to cancer treatment that combines nanotechnology and pharmacotherapy. It is an exciting and rich field of research to explore and optimize MWCNTs for drug delivery purposes, which could result in significant benefits for cancer patients.
RESUMEN
CONTEXT: Multiwalled carbon nanotubes (MWCNTs) functionalized with lysine via 1,3-dipolar cycloaddition and conjugated to galactose or mannose are potential nanocarriers that can effectively bind to the lectin receptor in MDA-MB-231 or MCF-7 breast cancer cells. In this work, a method based on molecular dynamics (MD) simulation was used to predict the interaction of these functionalized MWCNTs with doxorubicin and obtain structural evidence that allows a better understanding of the drug loading and release process. The MD simulations showed that while doxorubicin only interacted with pristine MWCNTs through π-π stacking interactions, functionalized MWCNTs were also able to establish hydrogen bonds, suggesting that the functionalized groups improve doxorubicin loading. Moreover, the elevated adsorption levels observed for functionalized nanotubes further support this enhancement in loading efficiency. MD simulations also shed light on the intratumoral pH-specific release of doxorubicin from functionalized MWCNTs, which is induced by protonation of the daunosamine moiety. The simulations show that this change in protonation leads to a lower absorption of doxorubicin to the MWCNTs. The MD studies were then experimentally validated, where functionalized MWCNTs showed improved dispersion in aqueous medium compared to pristine MWCNTs and, in agreement with the computational predictions, increased drug loading capacity. Doxorubicin-loaded functionalized MWCNTs demonstrated specific release of doxorubicin in tumor microenvironment (pH = 5.0) with negligible release in the physiological pH (pH = 7.4). Furthermore, doxorubicin-free MWNCT nanoformulations exhibited insignificant cytotoxicity. The experimental studies yielded nearly identical results to the MD studies, underlining the usefulness of the method. Our functionalized MWCNTs represent promising non-toxic nanoplatforms with enhanced aqueous dispersibility and the potential for conjugation with ligands for targeted delivery of anti-cancer drugs to breast cancer cells. METHODS: The computational model of a pristine carbon nanotube was created with the buildCstruct 1.2 Python script. The lysinated functionalized groups were added with PyMOL and VMD. The carbon nanotubes and doxorubicin molecules were parameterized using the general AMBER force field, and RESP charges were determined using Gaussian 09. Molecular dynamics simulations were carried out with the AMBER 20 software package. Adsorption levels were calculated using the water-shell function of cpptraj. Cytotoxicity was evaluated via a MTT assay using MDA-MB-231 and MCF-7 breast cancer cells. Drug uptake of doxorubicin and doxorubicin-loaded MWCNTs was measured by fluorescence microscopy.
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Doxorrubicina , Simulación de Dinámica Molecular , Nanotubos de Carbono , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Nanotubos de Carbono/química , Humanos , Lisina/química , Portadores de Fármacos/química , Células MCF-7 , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Línea Celular Tumoral , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificaciónRESUMEN
INTRODUCTION: Fatty acid synthase (FASN), is a key metabolic enzyme involved in fatty acid biosynthesis and is an essential target for multiple disease progressions like cancer, obesity, NAFLD, etc. Aberrant expression of FASN is associated with deregulated energy metabolism of cells in these diseases. AREA COVERED: This article provides a summary of the most recent developments in the discovery of novel FASN inhibitors with potential therapeutic uses in cancer, obesity, and other metabolic disorders such as nonalcoholic fatty liver disease from 2016 to the present. The recently published patent applications and forthcoming clinical data of FASN inhibitors from both academia and the pharma industries are also highlighted in this study. EXPERT OPINION: The implication of FASN in multiple diseases has provided an impetus for developing novel inhibitors by both pharma companies and academia. Critical analysis of the patent literature reveals the exploration of diverse molecular scaffolds to identify potential FASN inhibitors that target the different catalytic domains of the enzyme. In spite of these multifaceted efforts, only one molecule, TVB-2640, has reached phase II trials for nonalcoholic steatohepatitis (NASH) and many malignancies. However, thecombined efforts of pharma companies to produce several FASN inhibitors might facilitate the clinical translation of this unique class of inhibitors. Nevertheless, concerted efforts towards developing multiple FASN inhibitors by pharma companies might facilitate the clinical translation of this novel class of inhibitors.
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Fatty acid synthase (FASN) is one of the enzymes required for fatty acid biosynthesis and is expressed as low or absent in most normal cells/tissues. However, this enzyme is upregulated in various cancer cells; hence, it can act as an important target to design and develop novel FASN inhibitors for cancer therapy. In the present investigation, a series of structurally diverse compounds that possessed FASN inhibitory activities were subjected to classification analysis using different algorithms such as support vector machine, decision tree, Naïve Bayes and random forest. The physicochemical descriptors and MACCS fingerprints were calculated using PaDEL software, and the WEKA software was utilized for the classification model building. The statistical parameters/confusion matrix calculated from the analysis revealed that the selected models have significant predictive performances. The results showed that the topological properties of the molecules are the main determinant for the activity classification. The key descriptors comprised of hydrogen bonding groups, especially acceptor (nHBAcc, minHBint9, minHBint5 and nwHBa), charge on the topological surface of the molecules (JGI10 & GGI2), ionization potential (GATS5i and GATS1i) and branching and distance between the groups (ETA_Eta_B_RC) are significantly contributed in the classification models. Further, the presence of heteroatoms (MACCSFP82, MACCSFP93 and MACCSFP131), especially nitrogen atom(s) and hydrogen bond acceptor groups (N-N group, NC(=O)N, N-C(=O)), actively contributed to the inhibitory activities. The results concluded that the topological polar properties concentrated in a specific region have significant FASN inhibitory activity. Hence, these results shall be used to develop novel molecules with increased FASN inhibitory activity.
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Algoritmos , Programas Informáticos , Teorema de Bayes , Bosques Aleatorios , Ácido Graso SintasasRESUMEN
Pancreatic cancer is a devastating disease with a low survival rate and limited treatment options. Graphene quantum dots (GQDs) have recently become popular as a promising platform for cancer diagnosis and treatment due to their exceptional physicochemical properties, such as biocompatibility, stability, and fluorescence. This review discusses the potential of multifunctional GQDs as a platform for receptor targeting, drug delivery, and bioimaging in pancreatic cancer. The current studies emphasized the ability of GQDs to selectively target pancreatic cancer cells by overexpressing binding receptors on the cell surface. Additionally, this review discussed the uses of GQDs as drug delivery vehicles for the controlled and targeted release of therapeutics for pancreatic cancer cells. Finally, the potential of GQDs as imaging agents for pancreatic cancer detection and monitoring has been discussed. Overall, multifunctional GQDs showed great promise as a versatile platform for the diagnosis and treatment of pancreatic cancer. Further investigation of multifunctional GQDs in terms of their potential and optimization in the context of pancreatic cancer therapy is needed.
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Grafito , Neoplasias Pancreáticas , Puntos Cuánticos , Humanos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Neoplasias PancreáticasRESUMEN
Protein tyrosine phosphatase 1B (PTP1B) has gained interest as a therapeutic target for type 2 diabetes and obesity. Besides metabolic signalling, PTP1B is a positive regulator of signalling pathways linked to ErbB2-induced breast tumorigenesis. Substantial evidence proves that its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. Therefore, huge research is being carried out on PTP1B inhibitors and their activity against breast cancer development. To date, only two PTP1B inhibitors, viz. ertiprotafib and trodusquemine, have entered clinical trials. The discovery of selective inhibitors of PTP1B could open a new avenue in breast cancer treatment. In this review, we provide an extensive overview on the involvement of PTP1B in breast cancer, its pathophysiology, with special attention on the discovery and development of various natural as well as synthetic PTP1B inhibitors. This study will provide significant information to the researchers developing PTP1B inhibitors for breast cancer treatment.
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Microwave-assisted synthetic methods have emerged as a popular technique for surface modification and the functionalization of multi-walled carbon nanotubes (MWCNTs) for diverse drug delivery applications. Microwave-induced functionalization of MWCNTs provides a high functionalization and requires less time than conventional techniques. Microwave methods are simple, fast, and effective for the covalent and noncovalent conjugation of MWCNTs with various biomolecules and polymers. The present review focuses on the synthetic and drug delivery applications of microwave irradiation techniques (MITs) for the functionalization of MWCNTs, using amino acids and other molecular frameworks containing amino groups, vitamins, proteins, epoxy moieties, metal nanoparticles, and polymers.
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In men, prostate cancer (PC) is the most frequently diagnosed cancer, causing an estimated 375,000 deaths globally. Currently, existing therapies for the treatment of PC, notably metastatic cases, have limited efficacy due to drug resistance and problematic adverse effects. Therefore, it is imperative to discover and develop novel drugs for treating PC that are efficacious and do not produce intolerable adverse or toxic effects. Condensed quinolines are naturally occurring anticancer compounds. In this study, we determined the in vitro efficacy of IND-2 (4-chloro-2-methylpyrimido[1â³,2â³:1,5]pyrazolo[3,4-b]quinolone) in the PC lines, PC-3 and DU-145. IND-2 significantly inhibited the proliferation of PC-3 and DU-145, with IC50 values of 3 µM and 3.5 µM, respectively. The incubation of PC-3 cells with 5 and 10 µM of IND-2 caused the loss of the mitochondrial membrane potential in PC-3 cells. Furthermore, IND-2, at 5 µM, increased the expression of cleaved caspase-3, cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase (PARP). The incubation of PC-3 cells with 5 µM of IND-2 significantly decreased the expression of the apoptotic protein, B-cell lymphoma 2 (Bcl-2). Furthermore, 5 and 10 µM of IND-2 produced morphological changes in PC-3 cells characteristic of apoptosis. Interestingly, IND-2 (2.5, 5 and 10 µM) also induced mitotic catastrophe in PC-3 cells, characterized by the accumulation of multinuclei. The incubation of DU-145 cells with 1.25 and 5 µM of IND-2 significantly increased the levels of reactive oxygen species (ROS). Finally, IND-2, at 10 µM, inhibited the catalytic activity of topoisomerase IIα. Overall, our findings suggest that IND-2 could be a potential lead compound for the development of more efficacious compounds for the treatment of PC.
RESUMEN
The emergence and rapid spread of novel coronavirus disease (COVID-19) has posed a serious challenge to global public health in 2020. The speed of this viral spread together with the high mortality rate has caused an unprecedented public health crisis. With no antivirals or vaccines available for the treatment of COVID-19, the medical community is presently exploring repositioning of clinically approved drugs for COVID-19. Chloroquine (CQ) and hydroxychloroquine (HCQ) have emerged as potential candidates for repositioning as anti-COVID-19 therapeutics and have received FDA authorization for compassionate use in COVID-19 patients. On March 28, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for HCQ in the treatment of COVID-19. However, it was later revoked by the FDA on June 15, 2020, after analyzing the emerging scientific data from ongoing clinical trials. Similarly, the World Health Organization (WHO) also conducted a Solidarity trial of chloroquine, hydroxychloroquine, remdesivir, lopinavir, and ritonavir. However, on May 23, 2020, the executive body of the "Solidarity trial" decided to put a temporary hold on the HCQ trial. On June 17, 2020, the WHO abruptly stopped the Solidarity trial of HCQ. The current review strives to examine the basis of compassionate use of CQ and HCQ for the treatment of COVID-19 in terms of literature evidence, establishing the antiviral efficacy of these drugs against corona and related viruses. Furthermore, the review presents a critical analysis of the clinical trial findings and also provides an insight into the dynamically changing decision on the authorization and withdrawal of HCQ as anti-COVID-19 therapy by the U.S. FDA and the WHO. Ultimately, our study necessitates an evidenced-based treatment protocol to confront the ongoing COVID-19 pandemic and not the mere observational study that mislead the public healthcare system, which paralyzes the entire world.