RESUMO
Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
Assuntos
Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Mariposas , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Células Tumorais CultivadasRESUMO
Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.
Assuntos
Caseína Quinase I/antagonistas & inibidores , Imidazóis/farmacologia , Leishmania major/enzimologia , Pirazinas/farmacologia , Tripanossomicidas/farmacologia , Caseína Quinase I/metabolismo , Humanos , Imidazóis/química , Leishmania major/efeitos dos fármacos , Leishmania major/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Tripanossomicidas/químicaRESUMO
Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 µM and 11.38 µM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 µM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 µM).
RESUMO
BACKGROUND: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Nitrocompostos/farmacologia , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Adulto , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
In a context of growing resistance to classical antifungal therapy, the design of new drugs targeting alternative pathways is highly expected. Benzofuro[3,2-d]pyrimidine derivatives, derived from (-)-cercosporamide, were synthesized and evaluated as potential Candida albicans PKC inhibitors in the aim of restoring susceptibility to azole treatment. Co-administration assay of benzofuropyrimidinedione 23 and fluconazole highlighted a synergistic effect on inhibition of cell growth of a Candida albicans resistant strain.
Assuntos
Antifúngicos/farmacologia , Benzofuranos/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/farmacologia , Antifúngicos/síntese química , Ascomicetos/química , Benzofuranos/síntese química , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Sinergismo Farmacológico , Fluconazol/síntese química , Fluconazol/farmacologia , Células HeLa , Humanos , Inibidores de Proteínas Quinases/síntese química , Pirimidinonas/síntese químicaRESUMO
Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evaluated against two breast cancer cell lines. Subsequently, cell cycle progression and apoptosis were conducted on best candidates, finally Western Blot analysis was performed to measure their ability to induce degradation of Hsp90 client proteins.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Terapia de Alvo Molecular , Naftiridinas/química , Naftiridinas/farmacologia , Aminas/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e HidrofílicasRESUMO
A series of (imidazo[1,2-a]pyrazin-6-yl)ureas were synthesized through 6-aminoimidazo[1,2-a]pyrazine as a key intermediate. 1-(Imidazo[1,2-a]pyrazin-6-yl)-3-(4-methoxy - phenyl)urea displayed a cytostatic activity against a non-small cell lung cancer cell line and was chosen for further mechanistic studies. Growth kinetics highlighted a selective dose-dependent response of P53-mutant NSCLC-N6-L16 cell line and overexpression of TP53 gene induced by this compound. These pharmacological data suggest a promising reactivation of p53 mutant in NSCLC-N6-L16 cell line.
Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Células 3T3 BALB , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Proteína Supressora de Tumor p53/genéticaRESUMO
A series of original 2-phenyl-3-(pyridin-4-yl)imidazo[1,2-a]pyrazines and the 3-iodo precursors, bearing a polar moiety at the C-8 position, was synthesized and evaluated for their antileishmanial activities. Two derivatives exhibited very good activity against the promastigote and the amastigote forms of Leishmania major in the micromolar to submicromolar ranges, coupled with a low cytotoxicity against macrophages and 3T3 mouse fibroblast cells. Through LmCK1 inhibition assay, investigations of the putative molecular target of these promising antileishmanial compounds will be discussed.
Assuntos
Antiprotozoários/farmacologia , Fibroblastos/efeitos dos fármacos , Imidazóis/farmacologia , Leishmania major/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Pirazinas/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
A novel series of 3-methyl-1-benzofuran derivatives were synthesized and screened in vitro for their antiproliferative activity against two human NSCLC cell lines (NSCLC-N6 mutant p53 and A549 wild type p53). Most promising compounds presented a structural analogy with the west part of cercosporamide, a natural product of biological interest. In particular, compounds 10, 12 and 31 showed cytotoxic activities at micromolar concentrations (IC50 < 9.3 µM) and compounds 13, 18 and 32 displayed moderate IC50 values (25-40 µM).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzofuranos/síntese química , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of 2,3-diarylimidazo[1,2-a]pyridines was synthesized and evaluated for their antileishmanial activities. Four derivatives exhibited good activity against the promastigote and intracellular amastigote stages of Leishmania major, coupled with a low cytotoxicity against the HeLa human cell line. The impact of compound lipophilicity on antiparasitic activities was investigated by Log D comparison. Although LmCK1 could be the parasitic target for three compounds (13, 18, 21), the inhibition of another target is under study to explain the antileishmanial effect of the most promising compounds.
Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Leishmania major/enzimologia , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Neurosteroids have been reported to modulate memory processes in rodents. Three analogues of dehydroepiandrosterone (DHEA), two of them previously described (7beta-aminoDHEA and 7beta-amino-17-ethylenedioxy-DHEA), and a new one (3beta-hydroxy-5alpha-androstane-6,17-dione) were synthesized, and their effects were evaluated on memory. This study examined their effects on long term and short term memory in male (6 weeks old) NMRI mice in comparison with the reference drug. Long term memory was assessed using the passive avoidance task and short term memory (spatial working memory) using the spontaneous alternation task in a Y maze. Moreover, the effects of DHEA and its analogues on spontaneous locomotion were measured. In all tests, DHEA and analogues were injected at three equimolar doses (0.300-1.350-6.075 microM/kg). DHEA and its three analogues administered immediately post-training at the highest doses (6.075 microM/kg, s.c.) improved retention in passive avoidance test. Without effect per se in the spatial working memory task, the four compounds failed to reverse scopolamine (1mg/kg, i.p.)-induced deficit in spontaneous alternation. These data suggested an action of DHEA and analogues in consolidation of long term memory particularly when emotional components are implied. Moreover, data indicated that pharmacological modulation of DHEA as performed in this study provides derivatives giving the same mnemonic profile than reference molecule.
Assuntos
Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/farmacologia , Etiocolanolona/análogos & derivados , Memória/efeitos dos fármacos , Memória/fisiologia , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Amnésia/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Desidroepiandrosterona/química , Desidroepiandrosterona/uso terapêutico , Etiocolanolona/farmacologia , Etiocolanolona/uso terapêutico , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Camundongos , Atividade Motora/efeitos dos fármacos , Escopolamina/farmacologiaRESUMO
The stilbene derivative 1,2,3-trimethoxy-4-[(E)-2-phenylvinyl]benzene, C(17)H(18)O(3), (I), and its homocoupling co-product (E,E)-1,4-bis(2,3,4-trimethoxyphenyl)buta-1,3-diene, C(22)H(26)O(6), (II), both have double bonds in trans conformations in their conjugated linkages. In the structure of stilbene (I), the aromatic rings deviate significantly from coplanarity, in contrast with coproduct (II), the core of which is rigorously planar. The deviation in stilbene (I) seems to be driven by intermolecular electrostatic interactions. Diene (II) sits on a crystallographic inversion centre, which bisects the conjugated linkage.
Assuntos
Alcadienos/química , Butadienos/química , Estilbenos/química , Compostos de Vinila/química , Cristalografia por Raios X , Conformação MolecularRESUMO
Six new synthetic bile acid derivatives were synthesized and tested in vitro against various human cancer cells (glioblastoma multiforme (GBM), multiple myeloma (KMS-11), and colonic carcinoma (HCT-116) cell lines. The best activity was obtained with compound IIIb on multiple myeloma cells (LD(50): 8.5+/-0.5 microM). This activity was associated with Mcl-1 and PARP-1 cleavage, inhibition of NFkappaB signaling, and DNA fragmentation, demonstrating an apoptotic cell death signaling pathway.
Assuntos
Amidas/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Ácido Litocólico/farmacologia , Neoplasias , Piperazinas/farmacologia , Amidas/síntese química , Western Blotting , Linhagem Celular Tumoral , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/síntese química , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fragmentação do DNA , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Ácido Litocólico/análogos & derivados , Ácido Litocólico/síntese química , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Piperazinas/síntese química , Transdução de SinaisRESUMO
Nine usnic acid-amine conjugates were evaluated on murine and human cancer cell lines. The polyamine derivatives showed significant cytotoxicity in L1210 cells. Their activities appeared to be independent of the polyamine transport system (PTS). Indeed, their activities were similar in chinese hamster ovary (CHO) and in the PTS deficient CHO-MG cells. In addition, alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor known to indirectly enhance the activity of the PTS and consequently increase the cytotoxicity of cytotoxic drugs entering cells via the PTS, had no effect on the activity of the polyamine derivatives. The more active derivative (1,8-diaminooctane derivative) displayed similar activities on all cancer cell lines studied and induced apoptosis.
Assuntos
Antineoplásicos/química , Benzofuranos/química , Benzofuranos/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Células CHO , Proteínas de Transporte , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Humanos , Camundongos , Poliaminas , Relação Estrutura-AtividadeRESUMO
A feasibility and chemical study of the coupling conditions of L-ascorbic acid with ferulic acid derivatives are described on the basis of the known synergistic effects of mixtures of various antioxidants. Novel L-ascorbic ferulic hybrids linked at the C-3 hydroxyl group were prepared with the aim to protect the alcohol function and the enediol system.
Assuntos
Antioxidantes , Ácido Ascórbico , Ácidos Cumáricos , Antioxidantes/síntese química , Antioxidantes/química , Ácido Ascórbico/síntese química , Ácido Ascórbico/química , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/química , Humanos , Estrutura Molecular , Oxidantes/química , Estresse OxidativoRESUMO
Efficient syntheses of new DHEA analogues, and their apoptotic and necrotic effects on Leydig cells and TM4 Sertoli cells are described. The key step in the synthetic strategy of 7-amino-DHEA derivatives involves a bromination on C-7 position to give an epimeric mixture of bromides which were substituted by azides and reduced to give 7alpha- and 7beta-amino-3beta-hydroxyandrost-5-en-17-ones. No cytotoxic effect induced by apoptosis mechanism was observed on Leydig and TM4 Sertoli cells by treatment with these amino-DHEA analogues. A necrotic effect was induced only in TM4 Sertoli cells. The best activity was obtained with 7alpha,beta-amino-androst-5-en-3beta-ol and 7beta-amino-3beta-hydroxy-androst-5-en-17-one.
Assuntos
Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/síntese química , Desidroepiandrosterona/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Células de Sertoli/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Desidroepiandrosterona/química , Relação Dose-Resposta a Droga , Masculino , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Two sterol families have been synthesized: the first one is nitrogenous sterols containing amino, N-hydroxyimino or cyano group and the second one is oxysterols such as ketosterol and hydroxysterols. These compounds were then evaluated in vitro against Leishmania donovani promastigotes and Trypanosoma brucei brucei trypomastigotes. The most active compounds against L. donovani promastigotes were 7beta-aminomethylcholesterol and 7alpha,beta-aminocholesterol (IC50 in a range from 1 to 3 microM, pentamidine: 2.8 microM). These compounds were active on intramacrophage amastigotes with IC50 of 1.3 microM. Such an activity justifies further in vivo antileishmanial evaluation. Against T. b. brucei, (24R,S)-24-hydroxy-24-methylcholesterol (MEC, 12.5 microM) was the most active compound from these series.