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1.
Bioorg Med Chem Lett ; 29(17): 2516-2524, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350126

RESUMO

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like. .


Assuntos
Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Lisina/química , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Mutação Puntual , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
2.
J Enzyme Inhib Med Chem ; 33(1): 1-8, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29098884

RESUMO

With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-ß that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-ß inhibiting properties. We identified dual inhibitors of both EGFR and PDGFR-ß in the nanomolar range which have been initially screened in cancer cell lines to prove a benefit of both EGFR and PDGFR-ß inhibition.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Relação Estrutura-Atividade
3.
Molecules ; 23(9)2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213139

RESUMO

The current number of drugs available for the treatment of Alzheimer's disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aß peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3ß, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau⁻tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3ß in nanomolar ranges.


Assuntos
Benzofuranos/síntese química , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Proteínas tau/metabolismo , Animais , Benzofuranos/química , Benzofuranos/farmacologia , Proteína Quinase CDC2/metabolismo , Células COS , Linhagem Celular , Chlorocebus aethiops , Quinase 4 Dependente de Ciclina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fosforilação/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Células Sf9 , Proteínas tau/química
4.
Bioorg Med Chem Lett ; 27(12): 2708-2712, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28478927

RESUMO

The quinazoline scaffold is the main part of many marketed EGFR inhibitors. Resistance developments against those inhibitors enforced the search for novel structural lead compounds. We developed novel benzo-anellated 4-benzylamine pyrrolopyrimidines with varied substitution patterns at both the molecular scaffold and the attached residue in the 4-position. The structure-dependent affinities towards EGFR are discussed and first nanomolar derivatives have been identified. Docking studies were carried out for EGFR in order to explore the potential binding mode of the novel inhibitors. As the receptor tyrosine kinase VEGFR2 recently gained an increasing interest as an upregulated signaling kinase in many solid tumors and in tumor metastasis we determined the affinity of our compounds to inhibit VEGFR2. So we identified novel dually acting EGFR and VEGFR2 inhibitors for which first anticancer screening data are reported. Those data indicate a stronger antiproliferative effect of a VEGFR2 inhibition compared to the EGFR inhibition.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
J Enzyme Inhib Med Chem ; 32(1): 271-276, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28097905

RESUMO

Novel 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines have been synthesized with varied substitution patterns both at the molecular scaffold of the benzo-anellated ring and at the 4-benzylamino residue. With a structural similarity to substituted thieno[2,3-d]pyrimidines as epidermal growth factor receptor (EGFR) inhibitors, we characterized the inhibition of EGFR for our novel compounds. As receptor heterodimerization gained certain interest as mechanism of cancer cells to become resistant against novel protein kinase inhibitors, we additionally measured the inhibition of insulin-like growth factor receptor IGF-1R which is a prominent receptor for such heterodimerizations with EGFR. Structure-activity relationships are discussed for both kinase inhibitions depending on the varied substitution patterns. We discovered novel dual inhibitors of both receptor tyrosine kinases with interest for further studies to reduce inhibitor resistance developments in cancer treatment.


Assuntos
Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptor IGF Tipo 1/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho
6.
Bioorg Med Chem Lett ; 24(8): 1948-51, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24650640

RESUMO

Dysregulation of cell signalling processes caused by an enhanced activity of protein kinases mainly contributes to cancer progression. Protein kinase inhibitors have been established as promising drugs that inhibit such overactive protein kinases in cancer cells. The formation of metastases, which makes a therapy difficult, remains a great challenge for cancer treatment. Recently, breast tumor kinase (Brk) was discovered as novel and interesting target for a cancer therapy because Brk participates in both cell dysregulation and metastasis. We discovered 4-anilino substituted α-carboline compounds as a novel class of highly active Brk inhibitors. In the current work, structure-activity relationships are discussed including docking results obtained for 4-anilino α-carbolines. A first profiling of selective kinase inhibition and a proof of concept for the antiproliferative effects is demonstrated. These results qualify the compounds as a promising class of novel antitumor agents.


Assuntos
Carbolinas/síntese química , Carbolinas/farmacologia , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Ativação Enzimática/efeitos dos fármacos , Humanos
7.
Bioorg Med Chem Lett ; 22(22): 6914-8, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23039927

RESUMO

Alzheimer disease (AD) turned out to be a multifactorial process leading to neuronal decay. So far merely single target structures which attribute to the AD progression have been considered to develop specific drugs. However, such drug developments have been disappointing in clinical stages. Multitargeting of more than one target structure determines recent studies of developing novel lead compounds. Protein kinases have been identified to contribute to the neuronal decay with CDK1, GSK-3ß and CDK5/p25 being involved in a pathological tau protein hyperphosphorylation. We discovered novel lead structures of the dihydroxy-1-aza-9-oxafluorene type with nanomolar activities against CDK1, GSK-3ß and CDK5/p25. Structure-activity relationships (SAR) of the protein kinase inhibition are discussed within our first compound series. One nanomolar active compound profiled as selective protein kinase inhibitor. Bioanalysis of a harmless cellular toxicity and of the inhibition of tau protein phosphorylation qualifies the compound for further studies.


Assuntos
Doença de Alzheimer/enzimologia , Compostos Aza/química , Fluorenos/química , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fluorenos/síntese química , Fluorenos/toxicidade , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/toxicidade , Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas tau/metabolismo
8.
Bioorg Med Chem ; 20(1): 125-36, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22169601

RESUMO

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC(50) values ranging form 0.3-1µM for compound 42, and 0.1-0.3µM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).


Assuntos
Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Indóis/química , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacologia , Fosforilação/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 20(23): 6915-9, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21035334

RESUMO

Recently the insuline-like growth factor receptor (IGF-1R) emerged as a promising target structure for the development of novel anti-cancer agents. IGF-1R plays a central role in both tumour progression and resistance development against anti-cancer drugs. We discovered 1-aza-9-oxafluorene derivatives as novel lead structures with submicromolar activities against IGF-1R. Structure-activity relationships (SARs) on a series of related receptor tyrosine kinases (RTKs) are discussed in the context of available crystal structures. A preliminary selectivity-profiling is demonstrated for the first compound series. Antiproliferative tumour cell line screening studies yielded one candidate as a promising cytostatic agent without significant toxic effects.


Assuntos
Benzilaminas/farmacologia , Descoberta de Drogas/métodos , Receptor IGF Tipo 1/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzilaminas/síntese química , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Ligação Proteica , Receptores Proteína Tirosina Quinases/química , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 19(5): 1349-56, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19211246

RESUMO

Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC(50) values in the nanomolar range on different kinases down to 63nM.


Assuntos
Benzotiazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Benzotiazóis/metabolismo , Sítios de Ligação/fisiologia , Inibidores de Proteínas Quinases/metabolismo
12.
J Nat Prod ; 72(4): 626-31, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19271717

RESUMO

The endophytic fungus Stemphylium globuliferum was isolated from stem tissues of the Moroccan medicinal plant Mentha pulegium. Extracts of the fungus, which was grown on solid rice medium, exhibited considerable cytotoxicity when tested in vitro against L5178Y cells. Chemical investigation yielded five new secondary metabolites, alterporriol G (4) and its atropisomer alterporriol H (5), altersolanol K (11), altersolanol L (12), stemphypyrone (13), and the known compounds 6-O-methylalaternin (1), macrosporin (2), altersolanol A (3), alterporriol E (6), alterporriol D (7), alterporriol A (8), alterporriol B (9), and altersolanol J (10). The structures were determined on the basis of one- and two-dimensional NMR spectroscopy and mass spectrometry. Among the alterporriol-type anthranoid dimers, the mixture of alterporriols G and H (4/5) exhibited considerable cytotoxicity against L5178Y cells with an EC(50) value of 2.7 microg/mL, whereas the other congeners showed only modest activity. The compounds were also tested for kinase inhibitory activity in an assay involving 24 different kinases. Compounds 1, 2, 3, and the mixture of 4 and 5 were the most potent inhibitors, displaying EC(50) values between 0.64 and 1.4 microg/mL toward individual kinases.


Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Ascomicetos/química , Mentha pulegium/microbiologia , Plantas Medicinais/microbiologia , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/farmacologia , Animais , Antraquinonas/química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Estrutura Molecular , Marrocos , Caules de Planta/microbiologia , Inibidores de Proteínas Quinases/química , Estereoisomerismo
13.
Cancer Res ; 67(17): 8325-34, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17804748

RESUMO

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Compostos Aza/química , Compostos Aza/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Células Cultivadas , Cristalografia por Raios X , Ciclina A/química , Ciclina A/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/química , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Avaliação Pré-Clínica de Medicamentos , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Modelos Moleculares , Ligação Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancers (Basel) ; 11(2)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791458

RESUMO

In this second study, we established syngeneic in vivo models named carcinogen-induced mouse-derived isografts (cMDIs). Carcinogen-induced tumors were obtained during short-term observation (3⁻9 months) of CBA/J mice treated with various administration routes with 3-methylcholanthrene (MCA) or N-methyl-N-nitrosourea (MNU) as carcinogens. During necropsy, primary tumors and suspicious tissues were assessed macroscopically and re-transplanted (in PDX-like manner) into sex-matched syngeneic animals. Outgrowing tumors were histologically characterized as either spinocellular carcinoma (1/8) or various differentiated sarcomas (7/8). Growth curves of four sarcomas showed striking heterogeneity. These cMDIs were further characterized by flow cytometry, RNA sequencing, or efficacy studies. A variable invasion of immune cells into the tumors, as well as varying expression of tyrosine kinase receptor, IFN-γ signature, or immune cell population marker genes could be observed. Immune checkpoint inhibitor treatment (anti-mPD-1, anti-mCTLA-4, or a combination thereof) showed different responses in the various cMDI models. In general, cMDI models are carcinogen-induced tumors of low passage number that were propagated as tissue pieces in mice without any tissue culturing. Therefore, the tumors contained conserved tumor characteristics and intratumoral immune cell populations. In contrast to the previously described spontaneous MDI, carcinogen induction resulted in a greater number of individual but histologically related tumors, which were preferentially sarcomas.

15.
Cancers (Basel) ; 11(2)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791466

RESUMO

Syngeneic in vivo tumor models are valuable for the development and investigation of immune-modulating anti-cancer drugs. In the present study, we established a novel syngeneic in vivo model type named mouse-derived isografts (MDIs). Spontaneous MDIs (sMDIs) were obtained during a long-term observation period (more than one to two years) of naïve and untreated animals of various mouse strains (C3H/HeJ, CBA/J, DBA/2N, BALB/c, and C57BL/6N). Primary tumors or suspicious tissues were assessed macroscopically and re-transplanted in a PDX-like manner as small tumor pieces into sex-matched syngeneic animals. Nine outgrowing primary tumors were histologically characterized either as adenocarcinomas, histiocytic carcinomas, or lymphomas. Growth of the tumor pieces after re-transplantation displayed model heterogeneity. The adenocarcinoma sMDI model JA-0009 was further characterized by flow cytometry, RNA-sequencing, and efficacy studies. M2 macrophages were found to be the main tumor infiltrating leukocyte population, whereas only a few T cells were observed. JA-0009 showed limited sensitivity when treated with antibodies against inhibitory checkpoint molecules (anti-mPD-1 and anti-mCTLA-4), but high sensitivity to gemcitabine treatment. The generated sMDI are spontaneously occurring tumors of low passage number, propagated as tissue pieces in mice without any tissue culturing, and thus conserving the original tumor characteristics and intratumoral immune cell populations.

16.
Int J Cancer ; 122(5): 1145-54, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17973264

RESUMO

The prostate-specific antigen (PSA) is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albumin-bound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062-4066). In this work, we describe an albumin-binding prodrug, EMC-Arg-Ser-Ser-Tyr-Tyr--Ser-Arg-DOXO [EMC: epsilon-Maleimidocaproic acid; DOXO = doxorubicin; X = amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water-solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA-positive tumors (LNCaP) demonstrated that the albumin-bound form of the prodrug was efficiently cleaved by PSA at the P(1)-P' (1) scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was approximately 100-fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 x 4 mg/kg caused significant weight loss and mortality (-25%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 x 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (+/-25%, **p = 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (-50%, SD +/- 115%, *p = 0.038).


Assuntos
Albuminas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Pró-Fármacos/síntese química , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Albuminas/metabolismo , Animais , Antibióticos Antineoplásicos/metabolismo , Modelos Animais de Doenças , Doxorrubicina/metabolismo , Humanos , Masculino , Camundongos , Camundongos SCID , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 28(2A): 933-41, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18507039

RESUMO

BACKGROUND: Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated. MATERIALS AND METHODS: The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration. RESULTS: Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2xd and 200 Bg/kg 1xd, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model. CONCLUSION: The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Ácido Clodrônico/uso terapêutico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Animais , Conservadores da Densidade Óssea/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases/metabolismo , Ácido Zoledrônico
18.
J Nat Prod ; 71(6): 972-80, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18494522

RESUMO

From the Egyptian medicinal plant Polygonum senegalense the fungal endophyte Alternaria sp. was isolated. Extracts of the fungus grown either in liquid culture or on solid rice media exhibited cytotoxic activity when tested in vitro against L5178Y cells. Chromatographic separation of the extracts yielded 15 natural products, out of which seven were new compounds, with both fungal extracts differing considerably with regard to their secondary metabolites. Compounds 1, 2, 3, 6, and 7 showed cytotoxic activity with EC 50 values ranging from 1.7 to 7.8 microg/mL. When analyzed in vitro for their inhibitory potential against 24 different protein kinases, compounds 1- 3, 5- 8, and 15 inhibited several of these enzymes (IC 50 values 0.22-9.8 microg/mL). Interestingly, compounds 1, 3, and 6 were also identified as constituents of an extract derived from healthy leaves of the host plant P. senegalense, thereby indicating that the production of natural products by the endophyte proceeds also under in situ conditions within the plant host.


Assuntos
Alternaria/química , Antineoplásicos/isolamento & purificação , Compostos de Bifenilo/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Lactonas/isolamento & purificação , Polygonum/microbiologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lactonas/química , Camundongos , Folhas de Planta/microbiologia
19.
Eur J Pharm Biopharm ; 126: 89-94, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28315448

RESUMO

Rearrangements of anaplastic lymphoma kinase (ALK) are associated with several cancer diseases. Due to resistance development against existing ALK-inhibitors, new, structurally unrelated inhibitors are required. By a scaffold hopping strategy, 6,8-disubstituted purines were designed as analogues of similar ALK-inhibiting thieno[3,2-d]pyrimidines. While the new title compounds indeed inhibited ALK and several ALK mutants in submicromolar concentrations, they retained poor water solubility.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Purinas/química , Purinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Humanos , Simulação de Acoplamento Molecular/métodos , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Purinas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 42(11-12): 1317-24, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17448574

RESUMO

The synthesis of 1-aryl-4,6-dihydropyrazolo[4,3-d][1]benzazepin-5(1H)-ones by cyclization of 4-[(dimethylamino)methylidene]-3,4-dihydro-1H-[1]benzazepine-2,5-dione with arylhydrazines is reported. When tested on a panel of human cancer cell lines, the title compounds showed antiproliferative activity and a characteristic selectivity pattern of growth inhibition. Although structurally akin to established kinase inhibitors, the new compounds did not exhibit noteworthy inhibitory activity when tested on an array of cancer-related kinases.


Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Neoplasias da Mama/patologia , Leucemia/patologia , Benzazepinas/química , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Leucemia/enzimologia , Inibidores de Proteínas Quinases/química
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