RESUMO
c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.
Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Proto-Oncogênicas c-met , Fator de Transcrição STAT3 , Tiazóis , Humanos , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Simulação de Acoplamento MolecularRESUMO
Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC50 values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values in the range 0.76-21.5 µM, and they showed promising cytotoxic activity against PC-3 with IC50 values in the range 1.85-3.42 µM compared to cabozantinib (IC50 = 1.06 µM against MCF-7 and 2.01 µM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G2/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast cancer.
RESUMO
The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.
Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Isatina , Inibidores de Proteínas Quinases , Fator de Transcrição STAT3 , Triazóis , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Isatina/farmacologia , Isatina/química , Isatina/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.
Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Triazinas , Triazinas/química , Triazinas/farmacologia , Triazinas/síntese química , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Camundongos , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacosRESUMO
Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n, 6a-c, 7a-b, and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS-5m, endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC50 values range from 2.93 µM (MDA-MB-231) to 5.86 µM (A549). Furthermore, compound APBS-5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS-5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico, a molecular docking investigation was also carried out.
Assuntos
Antineoplásicos , Inibidores da Anidrase Carbônica , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indazóis , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/farmacologia , Sulfonamidas/química , Sulfonamidas/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Indazóis/farmacologia , Indazóis/síntese química , Indazóis/química , Proliferação de Células/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Cristalografia por Raios X , Estrutura Molecular , Relação Dose-Resposta a Droga , Camundongos , Linhagem Celular Tumoral , Reposicionamento de MedicamentosRESUMO
A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.
Assuntos
Antineoplásicos , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica , Cumarínicos , Simulação de Acoplamento Molecular , Tiazóis , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Camundongos , Cristalografia por Raios X , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Masculino , Antígenos de Neoplasias/metabolismoRESUMO
Type 2 diabetes (T2D) is the most common metabolic disorder. The undesirable effects of synthetic drugs demand a search for safe antidiabetic agents. This study aimed to assess the antidiabetic activity of different fractions of Atriplex halimus (petroleum ether 60-80, methylene chloride, ethyl acetate, and n-butanol) using Drosophila melanogaster larvae. Titers of total glucose and trehalose, as well as larval weight, were measured and compared with those of control and diabetic larvae. The expression of Drosophila insulin-like peptides (DILP2 and DILP3) and adipokinetic hormone (AKH) was evaluated. The results revealed a significant increase in total glucose, trehalose, and a decrease in body weight in the larvae fed a high-sugar diet compared with those in the control. When larvae fed diets containing the tested fractions, the total glucose and trehalose decreased to the control level, and the body weight increased. DILP2, DILP3, and AKH exhibited significant decreases upon treatment with A. halimus ethyl acetate. Metabolomic profiling of the ethyl acetate fraction of A. halimus revealed the presence of flavonoids and flavonoid glycosides. After docking screening to predict the most powerful moiety, we discovered that flavonoid glycosides (especially eriodictyol-7-O-neohesperidoside) have a greater affinity for the pocket than the other moieties. The results indicated the therapeutic activity of the A. halimus ethyl acetate fraction against induced T2D in Drosophila larvae. The antidiabetic activity may be attributed to flavonoids, which are the main components of the A. halimus ethyl acetate fraction.
Assuntos
Acetatos , Atriplex , Diabetes Mellitus Tipo 2 , Drosophila melanogaster , Hipoglicemiantes , Animais , Drosophila melanogaster/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Acetatos/química , Atriplex/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/veterinária , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Larva/efeitos dos fármacosRESUMO
In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives "5a-o". Results from the screening on A549 and MCF7 cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn't change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In light of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic indicators were studied.
Assuntos
Antineoplásicos , Receptores ErbB , Fator de Transcrição STAT3 , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound 7c disclosed the most potent activity (IC50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.
Assuntos
Glaucoma , Sulfonamidas , Humanos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sulfonamidas/química , Anidrase Carbônica II , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Inibidores da Anidrase Carbônica/química , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Glaucoma/tratamento farmacológico , Sulfanilamida , Anidrase Carbônica IX/metabolismoRESUMO
RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS's structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein's role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS-effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field's future.
RESUMO
New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.
Assuntos
Antineoplásicos , Anidrases Carbônicas , Humanos , Benzenossulfonamidas , Anidrase Carbônica IX/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Sulfonamidas/química , Anidrases Carbônicas/metabolismo , Antineoplásicos/química , Receptores ErbB/metabolismo , Isoformas de Proteínas/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Estrutura MolecularRESUMO
For the horseshoe tactic to succeed in inhibiting c-Met and Pim-1, the nicotinonitrile derivatives (2a-n) were produced in high quantities by coupling acetyl phenylpyrazole (1) with the proper aldehydes and ethyl cyanoacetate under basic conditions. Consistent basic and spectroscopic data (NMR, IR, Mass, and HPLC) supported the new products' structural findings. With IC50 potency in nanomolar ranges, these compounds had effectively repressed them, particularly compounds 2d and 2 h, with IC50 values below 200 nM. The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay. Similar to tivantinib, these compounds showed good antiproliferative properties against the HCT-116 tumor cells while having low cytotoxicity towards healthy fetal colon (FHC) cells. In the HCT-116 cell line, their ability to trigger the apoptotic cascade was also investigated by looking at the level of Bax and Bcl-2 as well as the activation of the proteolytic caspase cascade. When HCT-116 cells were exposed to compounds 2d and 2 h in comparison to the control, active caspase-3 levels increased. The HCT-116 cell line also upregulated Bcl-2 protein levels and downregulated Bax levels. Additionally, when treated with compound 2d, the HCT-116 cell cycle was primarily stopped at the S phase. Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.
Assuntos
Antineoplásicos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Proteína X Associada a bcl-2 , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Proliferação de Células , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases , ApoptoseRESUMO
Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, 6f achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.
Assuntos
Antineoplásicos , Telomerase , Feminino , Animais , Camundongos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Morte Celular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , ApoptoseRESUMO
The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI50 levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explainthe biological activities of the most potent compound.
Assuntos
Anti-Hipertensivos , Apoptose , Simulação de Acoplamento Molecular , Receptores ErbBRESUMO
Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFRWT, EGFRT790M, and EGFRL858R where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC50 = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.
New 32 hexahydroquinoline (HHQ) analogues 6ai, 8am, 10ad, and 12af having the same features of EGFR inhibitors were synthesised in racemic mixtures.The antiproliferative activities were assessed towards 60 cancer cell lines which were efficiently inhibited by compound 10c.Compound 10d remarkably inhibited EGFRWT, EGFRT790M, and EGFRL858R.Cell cycle analysis and Annexin V-based flow cytometry in the HOP-92 lung cancer cells were performed.The safety profile of compounds 10c and 10d was validated using normal human lung (IMR-90) cells.Molecular docking studies revealed that the S-isomers exhibited higher affinity than R-isomers to active sites.
Assuntos
Antineoplásicos , Neoplasias Pulmonares , Quinolinas , Humanos , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases/química , Quinolinas/químicaRESUMO
Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell carcinoma (HNSCC) subtype which is attributed to its reported multiple drug resistance (MDR). In the current study, we considered the essential pharmacophoric features of Dox as an effective Top. II inhibitor and sought to develop a novel set of imidazo[1,2-a] [1,3,5]triazin-2-amines (2a-2p) as a suggested anticancer option that could intercalate the DNA base pairs. We evaluated the % inhibition of the newly synthesized compounds on thirteen cancer cell lines and the analysis of structure-activity relationships revealed that the human head and neck cancer cell line (HNO97) was the most sensitive to their growth inhibition effect. Then, the IC50 values were recorded against the most sensitive cancer cell lines (HNO97, MDA-MB-231, and HEPG2), and compared to the normal cell line OEC (human oral epithelial cells). Compounds 2f and 2g showed very strong activities against HNO97 with IC50 values of (4 ± 1 and 3 ± 1.5 µg/mL), respectively, compared to that of Dox (9 ± 1.6 µg/mL). Next, a quantitative determination of human DNA Top. II concentrations in the most sensitive cell line (HNO97) were recorded for the most active anticancer derivatives. Again, compound 2f showed a superior Top. II inhibition with 87.86% compared to that of Dox (86.44%), while compound 2g achieved an inhibition of 81.37% which was close to the effect of Dox. To further investigate their effects on cell cycle progression and apoptosis induction in HNO97 cells, both 2f and 2g were selected for analysis. Both candidates arrested cell cycle progression at both the S and G2-M phases, as well as increased the early and late apoptosis phase ratios. Besides, both 2f and 2g were subjected to protein expression analysis of apoptosis-related genes (p53, BAX, IL-6, and BCL2). Moreover, the antioxidant effect of 2f and 2g was evaluated by measuring GSH, MDA, and NO markers in HNO97 cells. Furthermore, molecular docking for the newly designed tricyclic derivatives against both the Top. II and DNA double helix was carried out.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Inibidores da Topoisomerase II , Triazinas , Humanos , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologiaRESUMO
Acute myeloid leukemia (AML) stands as one of the most aggressive type of human cancer that can develop rapidly and thus requires immediate management. In the current study, the development of novel derivatives of pyrimido[1,2-a]benzimidazole (5a-p) as potential anti-AML agents is reported. The prepared compounds 5a-p were inspected for their in vitro anti-tumor activity at NCI-DTP and subsequently 5h was selected for full panel five-dose screening to assess its TGI, LC50 and GI50 values. Compound 5h showed effective anti-tumor activity at low micromolar concentration on all tested human cancer cell lines with GI50 range from 0.35 to 9.43 µM with superior sub-micromolar activity towards leukemia. Furthermore, pyrimido[1,2-a]benzimidazoles 5e-l were tested on a panel ofhuman acute leukemia cell lines, namely HL60, MOLM-13, MV4-11, CCRF-CEM and THP-1, where 5e-h reached single-digit micromolar GI50 values for all the tested cell lines. All prepared compounds were first tested for inhibitory action against the leukemia-associated mutant FLT3-ITD, as well as against ABL, CDK2, and GSK3 kinases, in order to identify the kinase target for the herein described pyrimido[1,2-a]benzimidazoles. However, the examined molecules disclosed non-significant activity against these kinases. Thereafter, a kinase profiling on a panel of 338 human kinases was then used to discover the potential target. Interestingly, pyrimido[1,2-a]benzimidazoles 5e and 5h significantly inhibited BMX kinase. Further investigation for the effect on cell cycle of HL60 and MV4-11 cells and caspase 3/7 activity was also performed. In addition, the changes in selected proteins (PARP-1, Mcl-1, pH3-Ser10) associated with cell death and viability were analyzed in HL60 and MV4-11 cells by immunoblotting.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Apoptose , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Tirosina Quinase 3 Semelhante a fms , Quinase 3 da Glicogênio Sintase , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Inibidores de Proteínas QuinasesRESUMO
In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.
Assuntos
Antineoplásicos , Anidrases Carbônicas , Isatina , Estrutura Molecular , Relação Estrutura-Atividade , Anidrases Carbônicas/metabolismo , Isatina/farmacologia , Isatina/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Antineoplásicos/farmacologia , Antineoplásicos/química , Sulfonamidas/farmacologia , Sulfonamidas/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Anidrase Carbônica IX , Antígenos de Neoplasias/metabolismoRESUMO
Researchers are constantly searching for drugs to combat the coronavirus pandemic caused by SARS-CoV-2, which has lasted for over two years. Natural compounds such as phenolic acids are being tested against Mpro and AAK1, which are key players in the SARS-CoV-2 life cycle. This research work aims to study the ability of a panel of natural phenolic acids to inhibit the virus's multiplication directly through Mpro and indirectly by affecting the adaptor-associated protein kinase-1 (AAK1). Pharmacophore mapping, molecular docking, and dynamic studies were conducted over 50 ns and 100 ns on a panel of 39 natural phenolic acids. Rosmarinic acid (16) on the Mpro receptor (- 16.33 kcal/mol) and tannic acid (17) on the AAK1 receptor (- 17.15 kcal/mol) exhibited the best docking energy against both receptors. These favourable docking score values were found to be superior to those of the co-crystallized ligands. Preclinical and clinical research is required before using them simultaneously to halt the COVID-19 life cycle in a synergistic manner.
Assuntos
COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , Humanos , Proteínas Adaptadoras de Transdução de Sinal , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oligonucleotídeos , SARS-CoV-2RESUMO
With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub- to two-digit micromolar potency (GI50 down to 0.3 µM and LC50 as low as 4 µM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 µM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics.