RESUMO
The design and synthesis of a new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids was accomplished. The in vitro cytotoxic potential of these new compounds was evaluated against lung cancer (A549), prostate cancer (PC-3, DU-145) and human embryonic kidney (HEK) cell lines. Compound 9p showed the highest potency on A549 cells with an IC50 value of 3.8 ± 0.02 µM. Moreover, 9p was found to be 25-fold more selective towards cancer cell lines than the non-cancerous (HEK) cell line. The target-based assay revealed the inhibition of the topoisomerase II enzyme by compound 9p. UV-visible spectroscopy, fluorescence, circular dichroism (CD), and viscosity studies inferred the intercalative property and effective binding of compound 9p with CT-DNA. Apoptosis induced by the compound 9p was observed by various morphological staining assays, i.e, DAPI, EtBr/AO. Further, the molecular modeling studies revealed the binding of compound 9p at the active site of the DNA-topoisomerase II complex while the physicochemical properties were in the recommended range. Finally, mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives can be considered as a promising scaffold for development as effective anticancer agents and topoisomerase II inhibitors.
Assuntos
Antineoplásicos , Inibidores da Topoisomerase II , Antineoplásicos/química , Apoptose , Proliferação de Células , DNA/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis , Pirimidinas , Relação Estrutura-AtividadeRESUMO
Efforts towards the development of potential anticancer agents, a new series of imidazo[1,2-a]pyridine-oxadiazole hybrids were synthesized and evaluated for their in vitro anticancer activity against lung cancer (A549) and prostate cancer (PC-3, DU-145) cell lines. Amongst the compounds tested, 6d showed the highest potency on A549 cells with an IC50 value of 2.8 ± 0.02 µM. Flow cytometric analysis of compound 6d treated A549 cells showed apoptosis induction by annexin-v/PI dual staining assay and the effect of 6d on different phases of cell cycle was also analyzed. Target based studies demonstrated the inhibition of tubulin polymerization by 6d at an IC50 value of 3.45 ± 0.51 µM and its effective binding with CT-DNA. Further, the molecular modelling studies revealed that 6d has a prominent binding affinity towards α/ß-tubulin receptor with admirable physico-chemical properties.
Assuntos
Antineoplásicos/farmacologia , DNA/química , Desenho de Fármacos , Microtúbulos/efeitos dos fármacos , Oxidiazóis/farmacologia , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Oxidiazóis/química , Polimerização/efeitos dos fármacos , Piridinas/química , Relação Estrutura-AtividadeRESUMO
An approach in modern medicinal chemistry to discover novel bioactive compounds is by mimicking diverse complementary pharmacophores. In extension of this strategy, a new class of piperazine-linked cinnamide derivatives of benzimidazole-pyrimidine hybrids have been designed and synthesized. Their in vitro cytotoxicity profiles were explored on selected human cancer cell lines. Specifically, structural comparison of target hybrids with tubulin-DAMA-colchicine and tubulin-nocodazole complexes has exposed a deep position of benzimidazole ring into the αT5 loop. All the synthesized compounds were demonstrated modest to interesting cytotoxicity against different cancer cell lines. The utmost cytotoxicity has shown with an amine linker of benzimidazole-pyrimidine series, with specificity toward A549 (lung cancer) cell line. The most potent compound in this series was 18i, which inhibited cancer cell growth at micromolar concentrations ranging 2.21-7.29 µM. Flow cytometry studies disclosed that 18i inhibited the cells in G2/M phase of cell cycle. The potent antitumor activity of 18i resulted from enhanced microtubule disruption at a similar level as nocodazole on ß-tubulin antibody, explored using immunofluorescence staining. The most active compound 18i also inhibited tubulin polymerization with an IC50 of 5.72 ± 0.51 µM. In vitro biological analysis of 18i presented apoptosis induction on A549 cells with triggering of ROS generation and loss of mitochondrial membrane potential, resulting in DNA injury. In addition, 18i displayed impairment in cellular migration and inhibited the colony formation. Notably, the safety profile of most potent compound 18i was revealed by screening against normal human pulmonary epithelial cells (L132: IC50: 69.25 ± 5.95 µM). The detailed binding interactions of 18i with tubulin was investigated by employing molecular docking, superimposition and free energy analyses. Thus remarks made in this study established that pyrimidine-benzimidazole hybrids as a new class of tubulin polymerization inhibitors with significant anticancer activity.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Cinamatos/química , Pirimidinas/química , Pirimidinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular , Desenho de Fármacos , Células HEK293 , Células Hep G2 , Humanos , Modelos Moleculares , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
In quest of promising anticancer agents, the pharmacophores of natural (ß-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 µM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 µM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Carbolinas/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Desenvolvimento de Medicamentos , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/química , Carbolinas/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
The unprecedented efficiency, reliability and adaptability in drug discovery, with the growing number of applications and impact, have made Click Chemistry fascinating to the scientific community. The specificity, biocompatibility along with other principles of click chemistry offers a reliable platform for the synthesis of drug-like molecules that can expedite the drug discovery process. This account summarizes such successes of versatile click reactions from our research group towards the development of functional molecules.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Química Click , Descoberta de Drogas , Oxindóis/farmacologia , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxindóis/química , Compostos de Espiro/químicaRESUMO
A ß-carboline directed regioselective C-H activation protocol for hydroxylation has been developed by employing Cu(OAc)2, a cost-effective 3d metal. This fastidious reaction proceeds under microwave irradiation and furnishes exclusively ortho-hydroxylated products with moderate to good yields under greener reaction conditions. Gratifyingly, this approach retains considerable functional group tolerance and is feasible on both electron-rich and electron-deficient substrates. This protocol signifies monohydroxylation on ß-carboline via C-H functionalization which leads into development of biologically relevant molecules. The reaction mechanism was confirmed by intercepting and characterizing all the proposed intermediates by ESI-QTOF-MS.
RESUMO
The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged ß-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a-k, with an IC50 < 5 µM in all the tested cancer cell lines (A549, MDA-MB-231, BT-474, HCT-116, THP-1) and the best cytotoxic potential was expressed in lung cancer cell line (A549) with an IC50 value of 2.82 ± 0.10 µM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 µM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 µM) with a selectivity index range of 14.9-25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
Assuntos
Antineoplásicos/química , Carbolinas/química , DNA Topoisomerases Tipo II/metabolismo , Indóis/química , Substâncias Intercalantes/química , Inibidores da Topoisomerase II/química , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/farmacologia , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilserinas/metabolismo , Tiadiazóis/química , Inibidores da Topoisomerase II/farmacologiaRESUMO
A Ru(II)-catalyzed regioselective C-H activation toward hydroxymethylation of ß-carbolines and isoquinolines as effective directing groups has been developed, and the mechanism was probed by using online electrospray ionization-tandem mass spectrometry. The introduction of the hydroxymethyl group in the biologically relevant molecules routed via C-H functionalization remains an important task. Gratifyingly, this protocol draws attention to the regioselective formation of monohydroxymethylated ß-carboline/isoquinoline products exclusively.
RESUMO
To explore a new set of cytotoxic agents, ß-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung cancer) cell line having IC50 value 1.01⯵M and 1.17⯵M respectively. Further, it was speculated that treatment with compound 10v may induce apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Bibenzilas/farmacologia , Carbolinas/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA de Cinetoplasto/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Células A549 , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Bibenzilas/química , Carbolinas/química , Proliferação de Células/efeitos dos fármacos , DNA de Cinetoplasto/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
An operationally simple Biginelli protocol was employed for the synthesis of new C6-carbon based aryl α-haloacrylamide-linked dihydropyrimidinone derivatives. The synthesized compounds were appraised for their in vitro antiproliferative potential against a selected panel of human cancer cell lines especially MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), HCT-116 (human colon cancer), HCT-15 (human colorectal adenocarcinoma), HT-29 (human colon adenocarcinoma) and DU145 (human prostate cancer) along with normal lung fibroblasts (HFL-1). Preferably, compounds containing α-haloacrylamide (10a-g) functionality were found to exhibit most significant cytotoxicity (IC50 value 0.54⯱â¯0.12 to 8.35⯱â¯0.82⯵M) against the listed cancer cell lines, particularly towards breast cancer cell lines MCF-7 and MDA-MB-231 (IC50 value 0.54⯱â¯0.12 to 3.70⯱â¯0.24⯵M). In the seam of synthesized compounds, compound 10f exhibited potent antiproliferative activity against breast cancer cell lines namely MCF-7 (IC50 value 0.54⯱â¯0.12⯵M) and MDA-MB-231 (IC50 value 1.18⯱â¯0.32⯵M). Further to understand the underlying apoptosis mechanisms, different staining techniques such as AO/EB, DCFDA, and DAPI staining were performed. To know the extent of apoptosis and loss of mitochondrial membrane potential in MCF-7 cell lines, annexin V-FITC/PI and JC-1 were performed. Cell cycle analysis revealed that compound 10f arrested the cells at G2/M phase in a dose-dependent manner. The compound 10f also found to exhibit significant inhibition of tubulin polymerization (IC50 of 6.91⯱â¯0.43⯵M) with microtubule destabilizing properties. Molecular docking studies also revealed that compound 10f efficiently interacted with critical catalytically active residues Ser178, Val238, and Val318 of the α/ß-tubulin by a hydrogen bond.
Assuntos
Desenho de Fármacos , Pirimidinonas/química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologiaRESUMO
A new series of 1,2,4-triazole-linked urea and thiourea conjugates have been synthesized and evaluated for their in vitro cytotoxicity against selected human cancer cell lines namely, breast (MCF-7, MDA-MB-231), lung (A549) prostate (DU145) and one mouse melanoma (B16-F10) cell line and compared with reference drug. The compound 5t showed significant cytotoxicity on MCF-7 breast cancer cell line with a IC50 value of 7.22⯱â¯0.47⯵M among all the tested compounds. Notably, induction of apoptosis by compound 5t on MCF-7 cells was evaluated using different staining techniques such as acridine orange/ethidium bromide (AO/EB), annexin V-FITC/PI, and DAPI. Further, clonogenic assay indicates the inhibition of colony formation on MCF-7 cells by compound 5t. Moreover, the flow-cytometric analysis also revealed that compound 5t caused the arrest of cells at G0/G1 phase of cell cycle. In addition, the compounds when tested on normal human cells (L-132) were found to be safer with low cytotoxicity profile.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Tioureia/química , Triazóis/química , Ureia/química , Células A549 , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Relação Estrutura-AtividadeRESUMO
A facile one-pot method for the synthesis of new phenanthrene fused-dihydrodibenzo-quinolinone derivatives has been successfully accomplished by employing sulfamic acid as catalyst. These new compounds were evaluated for their in vitro cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MCF-7) and colon (HT-29 and HCT-116) cancer cell lines. Among all the tested compounds, one of the derivatives 8p showed good anti-proliferative activity against A549 lung cancer cell line with an IC50 of 3.17⯱â¯0.52⯵M. Flow cytometric analyses revealed that compound 8p arrested both Sub G1 and G2/M phases of cell cycle in a dose dependent manner. The compound 8p also displayed significant inhibition of tubulin polymerization and disruption of microtubule network (IC50 of 5.15⯱â¯0.15⯵M). Molecular docking studies revealed that compound 8p efficiently interacted with critical amino acid Cys241 of the α/ß-tubulin by a hydrogen bond (SH Oâ¯=â¯2.4â¯Å). Further, the effect of 8p on cell viability was also studied by AO/EB, DCFDA and DAPI staining. The apoptotic characteristic features revealed that 8p inhibited cell proliferation effectively through apoptosis by inducing the ROS generation. Analysis of mitochondrial membrane potential through JC-1 staining and annexin V binding assay indicated the extent of apoptosis in A549 cancer cells.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Quinolonas/química , Ácidos Sulfônicos/química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/metabolismo , Células A549 , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fenantrenos/química , Estrutura Terciária de Proteína , Quinolonas/metabolismo , Quinolonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologiaRESUMO
A series of new C3-trans-cinnamide linked ß-carboline conjugates has been synthesized by coupling between various ß-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13-45â¯nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05â¯nM and 13.84â¯nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Cinamatos/química , DNA/efeitos dos fármacos , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Amidas/química , Animais , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Humanos , Substâncias Intercalantes/química , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , ViscosidadeRESUMO
Malignant melanoma is considered a deadly aggressive form of skin cancer that frequently metastasizes to various distal organs, which harbors mutations of the BRAF or NRAS which occur in 30 to 50% of melanoma patients. The growth factors secreted by melanoma cells contribute to tumor angiogenesis with the acquisition of metastatic potential by epithelial-mesenchymal transition (EMT) and drive melanoma growth toward a more aggressive form. Niclosamide (NCL) is an FDA-approved anthelmintic drug and is reported to have strong anti-cancer properties against various solid and liquid tumors. Its role in BRAF or NRAS mutated cells is unknown. In this context, we uncovered the role of NCL in impeding malignant metastatic melanoma in vitro in SK-MEL-2 and SK-MEL-28 cell lines. We found that NCL induces significant ROS generation and apoptosis through a series of molecular mechanisms, such as depolarization of mitochondrial membrane potential, arresting the cell cycle at the sub G1 phase with a significant increase in the DNA cleavage via topoisomerase II in both cell lines. We also found that NCL potently inhibited metastasis, which was examined by scratch wound assay, Additionally, we found that NCL inhibits the most important markers involved in the EMT signaling cascade that are stimulated by TGF-ß such as N-cadherin, Snail, Slug, Vimentin, α-SMA and p-Smad 2/3. This work provides useful insights into the mechanism of NCL in BRAF/NRAF mutant melanoma cells via inhibition of molecular signaling events involved in EMT signaling, and apoptosis induction.
Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Niclosamida/farmacologia , Transição Epitelial-Mesenquimal , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Apoptose , Linhagem Celular Tumoral , Mutação , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genéticaRESUMO
Knoevenagel condensation is an entrenched, prevailing, prominent arsenal following greener principles in the generation of α, ß-unsaturated ketones/carboxylic acids by involving carbonyl functionalities and active methylenes. This reaction has proved to be a major driving force in many multicomponent reactions indicating the prolific utility toward the development of biologically fascinating molecules. This eminent reaction was acclimatised on different pharmacophoric aldehydes (benzimidazole, ß-carboline, phenanthrene, indole, imidazothiadiazole, pyrazole etc.) and active methylenes (oxindole, barbituric acid, Meldrum's acid, thiazolidinedione etc.) to generate the library of chemical compounds. Their potential was also explicit to understand the significance of functionalities involved, which thereby evoke further developments in drug discovery. Furthermore, most of these reaction products exhibited remarkable anticancer activity in nanomolar to micromolar ranges by targeting different cancer targets like DNA, microtubules, Topo-I/II, and kinases (PIM, PARP, NMP, p300/CBP) etc. This review underscores the efficiency of the Knoevenagel condensation explored in the past six-year to generate molecules of pharmacological interest, predominantly toward cancer. The present review also provides the aspects of structure-activity relationships, mode of action and docking study with possible interaction with the target protein.
Assuntos
Antineoplásicos , Aldeídos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cetonas , Relação Estrutura-AtividadeRESUMO
A Ru(II)-catalyzed regioselective direct ortho-amidation of 2-aryl benzo[d]thiazoles employing acyl azides as a nitrogen source has been accomplished. This approach utilizes the efficiency of benzothiazole as a directing group and the role of acyl azide as an effective amidating agent toward C-N bond formation, thereby evading the general Curtius rearrangement. The protocol highlights significant functional group tolerance, single-step, and external oxidant-free conditions, with the release of only innocuous molecular nitrogen as the byproduct. The reaction mechanism and the intermediates associated with this selective Ru-catalyzed reaction have been investigated using ESI-MS. The protocol also aided in the construction of ortho-amidated ß-carbolines, unveiling another class of fluorescent molecules.
RESUMO
OBJECTIVE: To synthesize a series of phenanthrene-thiazolidinedione hybrids and explore their cytotoxic potential against human cancer cell lines of A-549 (lung cancer), HCT-116 and HT-29 (colon cancer), MDA MB-231 (triple-negative breast cancer), BT-474 (breast cancer) and (mouse melanoma) B16F10 cells. METHODS: A new series of phenanthrene-thiazolidinedione hybrids was synthesized via Knoevenagel condensation of phenanthrene-9-carbaldehyde and N-alkylated thiazolidinediones. The cytotoxicity (IC50) of the synthesized compounds was determined by MTT assay. Apoptotic assays like (AO/EB) and DAPI staining, cell cycle analysis, JC-1 staining and Annexin V binding assay studies were performed for the most active compound (Z)- 3-(4-bromobenzyl)-5-((2,3,6,7-tetramethoxyphenanthren-9-yl)methylene)thiazolidine-2,4-dione (17b). Molecular docking, dynamics and evaluation of pharmacokinetic (ADME/T) properties were also carried out by using Schrödinger. RESULTS AND DISCUSSION: From the series of tested compounds, 17b unveiled promising cytotoxic action with an IC50 value of 0.985±0.02µM on HCT-116 human colon cancer cells. The treatment of HCT-116 cells with 17b demonstrated distinctive apoptotic morphology like shrinkage of cells, horseshoe-shaped nuclei formation and chromatin condensation. The flow-cytometry analysis revealed the G0/G1 phase cell cycle arrest in a dosedependent fashion. The AO/EB, DAPI, DCFDA, Annexin-V and JC-1 staining studies were performed in order to determine the effect of the compound on cell viability. Computational studies were performed by using Schrödinger to determine the stability of the ligand with the DNA. CONCLUSION: The current study provides an insight into developing a series of phenanthrene thiazolidinedione derivatives as potential DNA interactive agents which might aid in colon cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Fenantrenos/farmacologia , Tiazolidinedionas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Fenantrenos/síntese química , Fenantrenos/química , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química , Células Tumorais CultivadasRESUMO
Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening with concomitant ring annulation using activated spiro-aziridines and heteroarenes. This method offers a new class of novel spiro-fused polycyclic pyrrolidines in a one-pot and sustainable manner with good yields and high diastereoselectivity. In addition, the structure of 3d was confirmed by single X-ray crystallography analysis.
RESUMO
The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 µM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/síntese química , Ureia/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their in vitro cytotoxicity on selected human cancer cell lines. Among them, derivatives 4a and 4b with the 6-aminobenzothiazole ring and 5g with the cinnamide ring displayed potent cytotoxic activity against colon (IC50: 3.715 and 3.467 µM) and lung cancer (IC50: 4.074 and 3.890 µM) cell lines when compared to amonafide (IC50: 5.459 and 7.762 µM). Later, the DNA binding studies for these selected derivatives (by CD, UV/vis, fluorescence spectroscopy, DNA viscosity, and molecular docking) suggested that these new derivatives significantly intercalate between two strands of DNA. In addition, the most potent derivatives 4a and 4b were also found to inhibit DNA topoisomerase-II.