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1.
Biomed Pharmacother ; 153: 113494, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076587

RESUMO

A range of novel 1,9-disubstituted ß-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. The preliminary study suggested that compounds 6a, 6b, 6c, 6d, 6e, 6f, 6g, and 6h tested in this study exerted potent antiproliferative effects on ten selected human tumor cell lines, with compound 6e being the most effective antiproliferative agent against the BGC-823, A375 and HT-29 cell lines, with IC50 values of 23.9, 9.3, and 3.6 µM, respectively. In addition, the antitumor capability of compound 6e was also evaluated in vivo, which demonstrated that compound 6e distinctly inhibited colorectal tumor growth in syngeneic BALB/c mice. Further research into the fundamental mechanism revealed that compound 6e inhibited colorectal cancer growth through the ATG5 (autophagy-related-5)/ATG7 (autophagy-related-7)-dependent autophagy pathway. This research can contribute to further clinical application of ß-carboline derivatives as new antitumor drugs.


Assuntos
Antineoplásicos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Curr Protoc ; 2(9): e529, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36066205

RESUMO

Tumor spheroid models are widely used for drug screening as in vitro models of the tumor microenvironment. There are various ways in which tumor spheroid models can be prepared, including the self-assembly of cells using low-adherent plates, micro-patterned plates, or hanging-drop plates. Recently, drug high-throughput screening (HTS) approaches have incorporated the use of these culture systems. These HTS culture systems, however, require complicated equipment, such as robot arms, detectors, and software for handling solutions and data processing. Here, we describe protocols that allow tumor spheroids to be tested with different concentrations of a drug in a parallel fashion using a microfluidic device that generates a gradient of anti-cancer drugs. This microfluidic spheroid culture device with a concentration gradient generator (µFSCD-CGG) enables the formation of 50 tumor spheroids and the testing of drugs at five different concentrations. First, we provide a protocol for the fabrication of the µFSCD-CGG, which has both a culture array in which tumor cells are injected and aggregate to form spheroids and a concentration gradient generator for drug testing. Second, we provide a protocol for tumor spheroid formation and HTS of anti-cancer drugs using the device. Finally, we provide a protocol for assessing the response of tumor spheroids at different drug concentrations. To address the needs of the pharmaceutical industry, this protocol can be used for various cell types, including stem cells, and the number of tumor spheroids and drug concentration ranges that can be tested in the µFSCD-CGG can be increased. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Fabrication of a microfluidic spheroid culture device with a concentration gradient generator (µFSCD-CGG) Basic Protocol 2: Seeding cells and formation of spheroids in the µFSCD-CGG Basic Protocol 3: Drug treatment and assessment of cell viability in the µFSCD-CGG.


Assuntos
Antineoplásicos , Dispositivos Lab-On-A-Chip , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala/métodos , Microfluídica/métodos , Esferoides Celulares
3.
Chem Pharm Bull (Tokyo) ; 70(9): 637-641, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36047235

RESUMO

Human epidermal growth factor (EGFR) is an important target for antitumor drug research. A series of novel quinazolinone derivatives were synthesized and developed as potent inhibitors of EGFR. The results showed that most of the aimed compounds had potential anti-tumor cell proliferation activities. Some compounds were tested for their EGFR inhibitory activity. Especially, compound 6d showed the most potent antitumor activity with IC50 values of 1.58 µM against human breast cancer (MCF-7) cell lines and exhibited the most potent EGFR inhibitory activity with IC50 of 0.77 µM. Docking simulation was performed to position compound 6d into the EGFR active site to determine the probable binding conformation.


Assuntos
Antineoplásicos , Quinazolinonas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinazolinonas/química , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 242: 114673, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36049275

RESUMO

A series of platinum compounds 2a-5a and 2b-5b with fluoro-functional groups are designed and synthesized. Among them, complex 2b is the most effective agent with 3-hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylate as a leaving ligand, which showed better cytotoxic activity than compounds containing only CF3 or OH group at 3-position of cyclobutane-1,1-dicarboxylate. The water solubility of 2a is better than that of carboplatin (32 mg/mL vs. 16 mg/mL), and its antitumor activity on A549 is 4.6-fold higher than that of carboplatin. The IC50 value of 2b on A549 cells is 4.73 ± 0.64 µM, which is comparable to that of oxaliplatin and higher than that of carboplatin. Meanwhile, 2a and 2b are less toxic than oxaliplatin and cisplatin toward BEAS-2B cells. Moreover, 2a and 2b induce cell apoptosis in vitro by the Bax-Bcl-2-caspase-3 pathway and ferroptosis through inhibiting GPx-4 and elevating COX2. Results from in vivo experiment show that the inhibition rate of A549 xenograft tumor is cisplatin > 2b > oxaliplatin > 2a > carboplatin.


Assuntos
Antineoplásicos , Ciclobutanos , Antineoplásicos/farmacologia , Carboplatina/farmacologia , Caspase 3 , Cisplatino/farmacologia , Ciclobutanos/farmacologia , Ciclo-Oxigenase 2 , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Platina , Água , Proteína X Associada a bcl-2
5.
Bioorg Chem ; 128: 106043, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36058118

RESUMO

Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase IIα inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Compounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 µM). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 µM) and 6c (IC50 = 2.35 µM) were comparable/ equipotent to Doxorubicin (IC50 = 2.71 µM) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 ± 0.13 µM, MCF7 IC50 = 1.137 ± 0.06 µM). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.


Assuntos
Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
6.
Bioorg Chem ; 128: 106117, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36063752

RESUMO

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.


Assuntos
Antineoplásicos , Proteínas Nucleares , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Cumarínicos/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Fatores de Transcrição
7.
J Enzyme Inhib Med Chem ; 37(1): 2530-2539, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36100238

RESUMO

A series of litseaone B analogues 4a∼4p were synthesised and antitumor activities of all compounds were screened. These compounds were designed by introducing different substituents on the B ring. Among these synthesised compounds, it was proved that 4k showed excellent activity against A549, HepG2, and HCT-15 cell lines, the IC50 values were 7.60 µM, 20.53 µM, and 4.59 µM, respectively. The results of tubulin polymerisation inhibition and immunofluorescence staining experiments displayed that 4k could act on tubulin and inhibit the polymerisation of tubulin. Moreover, the wound healing assay showed that 4k could inhibit the migration of A549 cells in a dose-dependent manner. Furthermore, the results of flow cytometry revealed that 4k was capable of blocking the cell cycle in the G2/M phase, inducing a decrease in the mitochondrial membrane potential and ultimately leading to apoptosis in A549 cells. Importantly, the possible binding model was also performed by molecular docking. Subject classification codes: short communication.


Assuntos
Moduladores de Tubulina , Tubulina (Proteína) , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides , Simulação de Acoplamento Molecular , Tubulina (Proteína)/metabolismo
8.
Bioorg Med Chem ; 72: 116976, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36067627

RESUMO

Colchicine binding site represent a crucial target for the anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 cancer cell lines and normal cell line HEK-293 T. In the series, 2­aryl group with 4­bromophenyl substitution displayed IC50 values of 6.37 µM, 17.43 µM, 6.76 µM and 4­chlorophenyl substitution displayed IC50 values of 2.16 µM, 8.53 µM, 10.42 µM against MCF-7, HELA and HT29 cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated apoptosis and lead molecule with 4­chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent anticancer agents.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Colchicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Polimerização , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
9.
Future Med Chem ; 14(19): 1349-1360, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36073363

RESUMO

Background: The 17-membered polyketide, lankacidin C, exhibits considerable antitumor activity as a microtubule stabilizer by binding to the paclitaxel binding site. Method: Esterification of the C-7/C-13 hydroxyl in lankacidin C was performed with acetyl, cinnamoyl and hydrocinnamoyl groups and their antitumor activity was assessed to improve the cytotoxicity of lankacidins through bioinspired computational design. Results: Compared with the cytotoxicity of parent lankacidin C against the HeLa cell line, 13-O-cinnamoyl-lankacidin C demonstrated sevenfold higher cytotoxicity. Furthermore, 7,13-di-O-cinnamoyl-lankacidin C exhibited considerable antitumor activity against three tested cell lines. Conclusion: C13-esterification by a cinnamoyl group dramatically improved antitumor activity, in agreement with computational predictions. This finding provides a potential substrate for next-generation lankacidin derivatives with significant antitumor activity.


Assuntos
Antibacterianos , Antineoplásicos , Antibacterianos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Macrolídeos/química , Macrolídeos/metabolismo , Paclitaxel/farmacologia , Relação Estrutura-Atividade
10.
Bioorg Med Chem ; 72: 116995, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36095945

RESUMO

Aiming to develop novel tropomyosin receptor kinase A (TrkA) inhibitors, a scaffold hopping strategy was utilized by transforming the fused indazole of Entrectinib to phenyl triazole/thiazole skeleton to obtain compounds 7a-7 h and 13a-13 h. In the light of MTT assay, phenyl triazole derivatives 7a-7 h exhibited moderate anti-proliferative activities against KM-12 cells with the IC50 values of 1.78-17.51 µM, while phenyl thiazole derivatives 13a-13 h showed the weaker efficacy. Further structure-guided optimizations by combining the phenyl triazole skeleton with 3,5­difluorophenyl and 3-carbamoyl-4-piperazinylaniline moiety led to compounds 19a-19d and 20. Eventually, 19c bearing (2-(4-methylpiperazin-1-yl)phenyl)(morpholino)methanone moiety exhibited excellent anti-proliferative activity on TrkA-positive KM-12 cells with IC50 value of 0.17 µM. Meanwhile, compound 19c showed the inhibitory potency on TrkA with IC50 value of 1.6 nM, and displayed higher selectivity on TrkA over TrkB (IC50 = 12.3 nM) and TrkC (IC50 = 18.4 nM). The dedicated wound healing and colony formation assay indicated that the optimal compound 19c could suppress migration and significantly inhibit KM-12 cell colony formation in a dose-dependent manner. In addition, 19c could weakly induce apoptosis of KM-12 cell in immunofluorescent staining analysis. Taken together, the above results suggest 19c as a novel TrkA inhibitor worthy of further profiling.


Assuntos
Antineoplásicos , Tiazóis , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indazóis/farmacologia , Estrutura Molecular , Morfolinos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologia , Triazóis/farmacologia , Tropomiosina/farmacologia
11.
J Med Chem ; 65(18): 12200-12218, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36097406

RESUMO

Both Src homology-2 domain-containing phosphatase 2 (SHP2) and histone deacetylase (HDAC) are important oncoproteins and potential immunomodulators. In this study, we first observed a synergistic antiproliferation effect of an allosteric SHP2 inhibitor (SHP099) and HDAC inhibitor (SAHA) in MV4-11 cells. Inspired by this result, a series of SHP2/HDAC dual inhibitors were designed based on the pharmacophore fusion strategy. Among these inhibitors, the most potent compound 8t showed excellent inhibitory activities against SHP2 (IC50 = 20.4 nM) and HDAC1 (IC50 = 25.3 nM). In particular, compound 8t exhibited improved antitumor activities compared with those of SHP099 and SAHA in vitro and in vivo. Our study also indicated that treatment with 8t could trigger efficient antitumor immunity by activating T cells, enhancing the antigen presentation function and promoting cytokine secretion. To our knowledge, we report the first small molecular SHP2/HDAC dual inhibitor and demonstrate a new strategy for cancer immunotherapy.


Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1 , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Monoéster Fosfórico Hidrolases , Relação Estrutura-Atividade
12.
Molecules ; 27(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36080127

RESUMO

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 µM, compared to tepotinib (IC50 = 0.013 µM). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G1 phase in a dose-dependent fashion.


Assuntos
Antineoplásicos , Apoptose , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
13.
Molecules ; 27(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36080141

RESUMO

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the ß-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC50 values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2).


Assuntos
Antineoplásicos , Neoplasias da Mama , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Paládio/química , Paládio/farmacologia , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
14.
Molecules ; 27(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36080261

RESUMO

Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive compounds with improved antiproliferative action. Compounds were characterized by elemental analysis, IR, and NMR spectroscopy. Density functional theory calculations with Becke's 3-parameter hybrid functional and 6-31+G(d,p) basis set were carried out to investigate the structural features of the ligands and Ga(III) complexes. Cytotoxic screening by MTT-dye reduction assay was carried out using cisplatin and melphalan as reference cytotoxic agents. A general formula [Ga(HL)2]NO3 for the complexes obtained was suggested. The complexes are mononuclear with the Ga(III) ions being surrounded by two ligands. The ligands acted as monoanionic tridentate (ONO) donor molecules. The analysis revealed coordination binding through deprotonated phenolic-oxygen, azomethine-nitrogen, and amide-oxygen atoms. The bioassay demonstrated that all compounds exhibited concentration-dependent antiproliferative activity at low micromolar concentrations against the acute myeloid leukemia HL-60 and T-cell leukemia SKW-3 cell lines. IC50 values of 5-bromo-derivative ligands and gallium (III) complexes are lower than those of cisplatin and much lower than these of melphalan. The coordination to gallium (III) additionally increased the cytotoxicity compared to the metal-free hydrazones.


Assuntos
Antineoplásicos , Complexos de Coordenação , Gálio , Aldeídos , Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Gálio/química , Gálio/farmacologia , Humanos , Ligantes , Melfalan , Oxigênio
15.
Molecules ; 27(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36080455

RESUMO

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 µM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 µM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 µM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.


Assuntos
Antineoplásicos , Tioglicosídeos , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/farmacologia , Humanos , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Tioglicosídeos/farmacologia , Triazóis/química
16.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955909

RESUMO

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias do Colo , Animais , Antineoplásicos/química , Carbamatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Esteroides/química , Relação Estrutura-Atividade
17.
Molecules ; 27(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35956848

RESUMO

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estaurosporina/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
18.
Molecules ; 27(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35956864

RESUMO

A variety of structurally different pyrimidines were synthesized. Elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy were used to confirm the chemical structures of all prepared compounds. The synthesized pyrimidines were screened against the growth of five human cancer cell lines (prostate carcinoma PC3, liver carcinoma HepG-2, human colon cancer HCT-116, human breast cancer MCF-7, human lung cancer A-549), and normal human lung fibroblasts (MRC-5) using MTT assay. Most of the screened pyrimidines have anti-proliferative activity on the growth of the PC3 cell line. Compounds 3b and 3d were more potent than the reference vinblastine sulfate (~2 to 3 × fold) and they can be considered promising leads for treating prostate cancer disease. Moreover, the screened compounds 3b, 3f, 3g, 3h, and 5 were assessed according to the values of their selectivity index (SI) and were found to be more selective and safer than vinblastine sulfate. Furthermore, using in silico computational tools, the physicochemical properties of all pyrimidine ligands were assessed, and the synthesized compounds fall within the criteria of RO5, thus having the potential to be orally bioavailable.


Assuntos
Antineoplásicos , Carcinoma , Compostos Heterocíclicos , Antineoplásicos/química , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Vimblastina/farmacologia
19.
Molecules ; 27(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35956876

RESUMO

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35-8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.


Assuntos
Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinoxalinas/química , Relação Estrutura-Atividade
20.
Molecules ; 27(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35956943

RESUMO

[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1-H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50 values of 9.47, 9.58 and 13.1 µM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade
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