RESUMO
A series of new benzimidazole-1,2,3-triazole hybrid derivatives have been synthesized via 'click' reaction and evaluated for their in vitro cytotoxicity as well as DNA binding affinity. MTT assay showed that all the six compounds are cytotoxic to PC3 and B16-F10 cancer cell lines. Though all the compounds showed moderate interaction with G4, c-Myc promoter DNA and dsDNA, 4f exhibited selective interaction with G-quadruplex DNA over duplex DNA as demonstrated by spectroscopic experiments like UV-vis spectroscopy, fluorescence spectroscopy, CD spectroscopy, thermal melting and fluorescence lifetime experiments. They also confirm the G-quadruplex DNA stabilizing potential of 4f. Viscosity measurements also confirm that 4f exhibits high G-quadruplex DNA selectivity over duplex DNA. Docking studies supported the spectroscopic observations. Cell cycle analysis showed that 4f induces G2/M phase arrest and induces apoptosis. Hence, from these experimental results it is evident that compound 4f may be a G-quadruplex DNA groove binding molecule with anticancer activity.
RESUMO
Apoptosis is an important phenomenon in multi cellular organisms for maintaining tissue homeostasis and embryonic development. Defect in apoptosis leads to a number of disorders like- autoimmune disorder, immunodeficiency and cancer. 21-22 nucleotides containing micro RNAs (miRNAs/miRs) function as a crucial regulator of apoptosis alike other cellular pathways. Recently, small molecules have been identified as a potent inducer of apoptosis. In this study, we have identified novel Triazole linked 2-phenyl benzoxazole derivatives (13j and 13h) as a negative regulator of apoptosis inhibiting micro RNAs (miR-2, miR-13 and miR-14) in a well established in vivo model Drosophila melanogaster where the process of apoptosis is very similar to human apoptosis. These compounds inhibit miR-2, miR-13 and miR-14 activity at their target sites, which induce an increased caspase activity, and in turn influence the caspase dependent apoptotic pathway. These two compounds also increase the mitochondrial reactive oxygen species (ROS) level to trigger apoptotic cell death.
Assuntos
Apoptose/genética , Benzoxazóis/farmacologia , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , MicroRNAs/genética , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Organogênese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Asas de Animais/citologia , Asas de Animais/efeitos dos fármacos , Asas de Animais/metabolismoRESUMO
A new series of 2-imino-4-thiazolidinone derivatives (7a-7t) has been synthesised and screened for their cytotoxicity against three cancer cell lines (B16F10, A549, PANC-1) and normal cell line (CHO). Among the compounds tested, compounds 7k, 7m, 7n showed potent cytotoxicity against B16F10 cell line with IC50 between 3.4 and 7µM. Interestingly these three compounds are non toxic to non cancerous CHO cells and induced apoptosis in B16F10 cells observed by DNA damage analysis through PI/Hoechst double staining method. Compounds 7k and 7n induced G0/G1 cell cycle arrest while compound 7m induced G2/M cell cycle arrest in B16F10 cells which confirms that these compounds have role in cancer cell cycle regulation. Additionally, compound 7m showed generation of intracellular reactive oxygen species (ROS) in B16F10 cells that may contribute in the cell cycle arrest whereas compounds 7k and 7n show anti-cancer activity through independent of ROS formation. Induction of apoptosis, cell cycle arrest in B16F10 cells are found to be the anti-cancer mechanism of these three compounds. The results all together demonstrate the potent cytotoxic nature of these compounds in cancer cells could be considered as new class of chemotherapeutic agents in near future.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , CamundongosRESUMO
A series of novel triazole linked N-(pyrimidin-2yl)benzo[d]thiazol-2-amine 5a-k were synthesized and evaluated for anticancer activity against breast (MCF-7), lung (A549) and skin (A375) cancer cell lines and their cytotoxic effects were compared against normal breast epithelial cells. The effect of compounds on cell cycle of MCF-7 breast cancer cell line was investigated by FACS. Result indicated G2/M cell cycle arrest of MCF-7 cells. Further promising compounds 5b, 5g, 5h and 5i were tested for their apoptosis inducing ability as well as inhibitory activity against key proteins NF-kB, Survivin, CYP1A1, and ERK1/2 which help in cancer cell survival and proliferation. The apoptotic aspect of these compounds is further evidenced by increase in the activity of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in highly malignant breast cancers and can be selected for further biological studies.
Assuntos
Antineoplásicos/síntese química , Tiazóis/química , Triazóis/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/metabolismo , 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 , Células MCF-7 , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/toxicidadeRESUMO
A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 µM, 0.409 µM and 0.653 µM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 µM.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/síntese química , Bases de Mannich/química , Peptidil Dipeptidase A/química , Triazóis/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Di-Hidropiridinas/química , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Bases de Mannich/síntese química , Bases de Mannich/farmacologia , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
A series of novel 2-(1H-indol-3-yl)-N-(3, 4-diphenylthiazol-2(3H)-ylidene) ethanamine derivatives (5a-o) were synthesized by cyclization of corresponding 1-(2-(1H-indol-3-yl) ethyl)-3-phenylthiourea 3 with 2-bromoacetophenone. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria and Gram-negative bacteria. In vitro antifungal activity also determined against the five fungal species. Structures of the synthesized compounds were established by elemental analysis and spectral data.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Fungos/efeitos dos fármacos , Tiazóis/químicaRESUMO
MicroRNAs are endogenously expressed tiny non-coding RNAs that control gene expression at the post-transcriptional level and regulate processes of cell growth, differentiation, proliferation and apoptosis. Aberrant expression of microRNAs correlates with various cancers. Our experiments demonstrated that imidazo-benzothiazole conjugates caused apoptosis in colon cancer cells by modulating the expression of microRNAs. In vivo study in Drosophila melanogaster has exhibited inhibitory action on bantam microRNA, the homolog of human miR-542-5p that is involved in deciding the cellular cues that regulate the balance between proliferation and apoptosis. The expression of direct targets of bantam such as Hid and HDAC-6 were affected upon compound treatment. Interestingly, these conjugates downregulate the genes involved in microRNA biogenesis such as Drosha, Pasha and Dicer-1. Our findings have elucidated the microRNA inhibitory role of imidazo-benzothiazole conjugates.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologiaRESUMO
A new series of isoxazoles and triazoles linked 2-phenyl benzothiazole were synthesized and evaluated for their anticancer activity. These compounds have been tested for their cytotoxicity three cancer cell lines. Among the compounds tested, compound 5d showed good cytotoxicity against Colo-205 and A549 cells in comparison to standard control PMX 610(1). Further compound 5d has been tested for its apoptotic activity and its inhibitory activity against caspase and PARP proteins. Hence this compound has the potential that it can be selected for further biological studies.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Triazóis/química , Triazóis/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoxazóis/síntese química , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Triazóis/síntese químicaRESUMO
Benzothiazolyl thiocarbamides has been achieved using a catalytic amount of 4-dimethylaminopyridine (DMAP) followed by its chemoselective oxidative cyclization with 1,3-di-n-butylimidazolium tribromide[bbim][Br(3)] to afford the N-bis-benzothiazole derivatives. All the synthesized compounds were evaluated for cytotoxic activity against two human monocytic cell lines (U 937, THP-1) and a mouse melanoma cell line (B16-F10). Based on their IC(50) values, the majority of the benzothiazolyl thiocarbamides and N-bis-benzothiazoles had significant antiproliferative activity on U 937 and B16-F10 cells, the compounds 3b, 3e, 3f, 3k, 6c and 6h were found to be the most active. The present findings indicate clearly that the compound 3e exhibited more antiproliferative activity on U 937 cells than the standard molecule, etoposide. Nevertheless, these compounds have shown comparatively less cytotoxicity towards THP-1 cells.
Assuntos
Benzotiazóis/síntese química , Química Farmacêutica/métodos , Tioureia/química , Animais , Antineoplásicos/farmacologia , Benzotiazóis/química , Catálise , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Melanoma Experimental/metabolismo , Camundongos , Modelos Químicos , Estrutura Molecular , Células U937RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) accounts for majority of liver cancers and is the leading cause of cancer related death in Asia. Like any other cancer, HCC develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and results in the loss of apoptosis. Therefore, a delicate balance between the expression of various genes involved in proliferation and apoptosis decide the ultimate fate of the cell to undergo rapid proliferation (cancer) or cell death. RESULTS: The benzothiazole based compounds exhibited effective cytotoxicity at 4 µM concentration and have shown G1 cell cycle arrest with decrease in levels of G1 cell cycle proteins such as cyclin D1 and Skp2. Involvement of tumour suppressor proteins such as PTEN and p53 was studied. Interestingly these compounds displayed decrease in the phosphorylated forms of AKT, p38 MAPK and ERK1/2 which play a vital role in cell proliferation. Compounds have exhibited strong and significant effect on the expression of micro RNAs such as miR-195a & miR-101-1 which regulate hepatic cell proliferation. CONCLUSIONS: The cell cycle arrest and apoptotic inducing nature of these compounds was revealed by FACS, BrdU cell proliferation and tunel assays. Compounds affected both tumour suppressor proteins as well as proteins that are involved in active cell proliferation. Micro RNAs whose target is Cyclin D1 such as miR-195a and miR-101-1 that is required for growth of hepatoma cells was drastically affected. These compounds caused apoptosis by activating caspase-3 and PARP.
RESUMO
A new series of Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles were synthesized and evaluated for their anti-cancer activity. These compounds showed better cytotoxicity activity with IC(50) values ranging from 2.8 to 8.0 µM in HepG2, MCF-7 and HeLa cell lines. Further mechanism aspects responsible for the anti-cancer activity of two promising compounds 3c and 3f in HepG2 cell line were studied. Interestingly, 3c, 3f induced G2/M cell cycle arrest with down regulation of cyclin B and up regulation of Chk2 protein. Moreover, compounds 3c, 3f also showed the characteristic features of apoptosis such as enhancement in the levels of caspase-3. Treatments with compounds led to a decrease in levels of vital cell proliferation proteins such as Jun (C-Jun, JunB), p38 MAPK, p-JNK and PKCα. The compound 3f of the series could be considered as the potential lead for its development as a novel anti-cancer agent.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Bases de Mannich/química , Tiazóis/síntese química , Tiazóis/farmacologia , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Tiazóis/químicaRESUMO
A series of beta-acetamido carbonyl compounds (S(1)-S(7)) were prepared using Dakin-West reaction from different substituted aldehyde and acetophenone in the presence of lanthanum triflate as a solid catalyst. All the compounds were tested for their alpha-glucosidase inhibitory potential against rat intestinal alpha-glucosidase. The most potent rat intestinal alpha-glucosidase inhibitors S(5) and S(7) were tested for their antihyperglycemic activity following carbohydrate tolerance test. Both the compounds displayed antihyperglycemic activity equivalent to the standard drug acarbose.