RESUMO
A series of 3,5-disubtituted pyridin-2(1H)-ones was synthesized. As part of a structure-activity relationship study performed in this series, structural modifications were based on 3-(indol-4-yl)-5-(pyridin-4-ylamino)pyridin-2(1H)-one B, which exhibited a potent anti-allodynic effect in a rat model of inflammatory pain. In this study, new compounds were assessed for their ability to inhibit cutaneous mechanical allodynia in rats by using the capsaicin pain model. Compound 36, a 2-methoxypyridine derivative, yielded the most promising outcome, demonstrating an enhanced analgesic effect.
RESUMO
Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3ß and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Inibidores de Proteínas Quinases/química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Pirazóis/química , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Tirosina Quinase 3 Semelhante a fms , Antineoplásicos/químicaRESUMO
Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4-g]quinazoline scaffold led to the discovery of DYRK/CLK binders with differential potency against individual enzyme isoforms. Exploring the structure-activity relationship within this chemotype, we demonstrated that two structurally close compounds, pyrido[3,4-g]quinazoline-2,10-diamine 1 and 10-nitro pyrido[3,4-g]quinazoline-2-amine 2, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound 1, compound 2 efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of 1 and 2 with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of 2 with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with 2 revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, 2 affected the genes that perform critical functions for cancer cells including DNA damage response, p53 signaling and transcription. Altogether, these results provide a mechanistic basis for the therapeutic efficacy of 2 previously demonstrated in in vivo GBM models.
RESUMO
A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC50 = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.
Assuntos
Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Pirróis , Inibidores de Proteínas Quinases/química , Pirróis/química , Relação Estrutura-Atividade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/farmacologiaRESUMO
A new series of pyrazolo[3,4-g]isoquinoline derivatives, diversely substituted at the 4- or 8-position, were synthesized. The results of the kinase inhibitory potency study demonstrated that the introduction of a bromine atom at the 8-position was detrimental to Haspin inhibition, while the introduction of an alkyl group at the 4-position led to a modification of the kinase inhibition profiles. Altogether, the results obtained demonstrated that new pyrazolo[3,4-g]isoquinolines represent a novel family of kinase inhibitors with various selectivity profiles.
Assuntos
Isoquinolinas , Isoquinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
We synthesized new analogues of the anti-AML agent VS-II-173. We studied the effect of the substitution at the 1- and 5-positions of the pyrazolo[4,3-a]phenanthridine scaffold on Pim-1 kinase inhibition and cytotoxicity against AML MOLM-13 cells. We found that compounds 20 and 21, substituted at the 1-position exhibited stronger Pim-1 inhibition together with a high potency toward MOLM-13 cells, associated with apoptosis induction and selectivity over non-cancerous NRK cells.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fenantridinas/farmacologia , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-pim-1RESUMO
Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Serina-Treonina Quinases , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new anti-allodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives. By substituting the pyridinone at the 3-position by various aryl/heteroaryl moieties and at the 5-position by a phenylamino group, we discovered that some derivatives exhibited a strong anti-allodynic potency in rats. Here, we report that varying the substitution of the pyridinone 5-position, the 3-position being substituted by an indol-4-yl moiety, further improves such anti-allodynic potency. Compared with 2, one of the two most active compounds of the first series, eleven out of nineteen newly synthetized compounds showed higher anti-allodynic potency, with two of them completely preventing mechanical allodynia. In the first series, hit compounds 1 and 2 appeared to be inhibitors of p38α MAPK, a protein kinase known to underlie pain hypersensitivity in animal models. Depending on the substitution at the 5-position, some newly synthetized compounds were also stronger p38α MAPK inhibitors. Surprisingly, though, anti-allodynic effects and p38α MAPK inhibitory potencies were not correlated, suggesting that other biological target(s) is/are involved in the analgesic activity in this series. Altogether, these results confirm that 3,5-disubstituted pyridine-2(1H)-one derivatives are of high interest for the development of new treatment of mechanical allodynia.
Assuntos
Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Animais , Adjuvante de Freund , Hiperalgesia/metabolismo , Estrutura Molecular , Medição da Dor , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridonas/síntese química , Piridonas/química , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR-Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.
Assuntos
Manejo da Dor , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Animais , Humanos , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.
Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Piridonas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Piridonas/síntese química , Piridonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Piridinas/química , Quinazolinas/química , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.
Assuntos
Desenho de Fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade , Quinases DyrkRESUMO
More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine, or pyrrolo[2,3-g]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 µmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase-mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML.
Assuntos
Carbazóis/química , Indazóis/química , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citarabina/química , Citarabina/farmacologia , Humanos , Indazóis/farmacologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/genética , Transdução de Sinais/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologiaRESUMO
The synthesis of new diversely substituted pyrido[3,4-g]quinazolines is described. The inhibitory potencies of prepared compounds toward a panel of five CMGC protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3), that are known to play a potential role in Alzheimer's disease, were evaluated. The best overall kinase inhibition profile was found for nitro compound 4 bearing an ethyl group at the 5-position.
Assuntos
Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Sítios de Ligação , Ativação Enzimática/efeitos dos fármacos , Nitrocompostos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/classificação , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Quinazolinas/químicaRESUMO
A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1-3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity.
Assuntos
Pirazóis/química , Estaurosporina/síntese química , Estaurosporina/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células K562 , Modelos Moleculares , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C-alfa/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Estaurosporina/química , Relação Estrutura-AtividadeRESUMO
This review, of the literature published between 2010 and 2015 reports that molecules containing a non-fused and/or fused pyrazole moiety could exhibit very potent activity toward Pim kinases, including the inhibition of cellular Bad phosphorylation as well as antiproliferative activity against various cancer cells. Even if Pim kinase inhibitors currently in clinical trial do not exhibit a pyrazole moiety, heteroaromatic kinase inhibitors containing an indazole part such as Axitinib and Pazopanib already reached the market. Therefore, one can imagine that in the future, heteroaromatic derivatives inhibiting Pim kinases including pyrazoles could be identified and used for their diagnostic and/or therapeutic potential alone or in combination with other drugs for the diseases in which Pim kinases are involved.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Descoberta de Drogas , Humanos , Modelos Moleculares , Terapia de Alvo Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirazóis/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Quinazolinas/síntese química , Quinazolinas/farmacologia , Sequência de Aminoácidos , Técnicas de Química Sintética , Cristalografia por Raios X , Humanos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
The synthesis of new indolopyrrolobenzodiazepine derivatives is described. Six compounds were selected for evaluation of cytotoxicity towards acute myeloid leukemia (AML) cells and normal fibroblasts. One compound (29) showed selective AML cell death induction. Its action was only partly overcome by knock-down of p53 or Bcl-2 overexpression, suggesting a strong activation of intrinsic apoptotic pathways.
Assuntos
Benzodiazepinas/química , Benzodiazepinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodiazepinas/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND AND METHODS: Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. RESULTS: We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. CONCLUSIONS: Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies.
Assuntos
Metástase Neoplásica/patologia , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CXCL12/metabolismo , Xenoenxertos , Humanos , Linfangiogênese/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-pim-1/biossíntese , Receptores CXCR4/metabolismo , Transplante Heterólogo , Peixe-ZebraRESUMO
The synthesis of new pyrrolocarbazoles substituted at N-1/N-10 positions is described. All the compounds tested demonstrated moderate to high Pim-1/Pim-3 kinase inhibitory potency. The most active inhibitors identified in this series (3, 17) have an alkyl chain bridging the N-1 and N-10 positions. These compounds (3, 17) exhibited apoptosis-inducing activity toward acute myeloid leukemia IPC-81 cells, but not toward normal fibroblasts.