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1.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299315

RESUMO

The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change -2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-ß (TGF-ß) signaling. Of interest, both drugs effectively downregulated "inhibitor of DNA binding, dominant negative helix-loop-helix" (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models.


Assuntos
Benzamidas/farmacologia , Citostáticos/farmacologia , Isoquinolinas/farmacologia , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tetra-Hidroisoquinolinas/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
2.
Eur J Med Chem ; 222: 113585, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118722

RESUMO

Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small molecule immuno-oncology agents, including retinoic acid-related orphan receptor gamma t (RORγt), chemokine receptor, stimulator of interferon genes (Sting), indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR), etc. Among them, the retinoic acid receptor-related orphan receptor γt (RORγt) has gradually attracted more attention in these years. In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study. In this work, starting from compound 7, compound 28 was obtained after 4 rounds of compound design, synthesis and SAR studies, which had an EC50 of 0.021 ± 0.002 µM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC50 of 0.021 ± 0.002 µM in mouse Th17 cell differentiation assay. It indicated that compound 28 had excellent RORγt agonistic activity and was expected to be developed as a new type of small molecule drug for cancer immunotherapy. The molecular dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramolecular interaction to stabilize H12, which helped RORγt to form the protein-binding site and therefore made the receptor ready to recruit coactivator. When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt.


Assuntos
Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
3.
Chem Biodivers ; 18(8): e2100261, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34170076

RESUMO

Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 µM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2) (IC50 =134.35±11.38 µM) exhibiting slightly better IC50 value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one (15) (IC50 =147.51±14.87 µM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (18) (IC50 =149.07±2.98 µM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (22) (IC50 =148.31±2.96 µM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.


Assuntos
Desoxirribonuclease I/antagonistas & inibidores , Inibidores Enzimáticos/química , Tetra-Hidroisoquinolinas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Desoxirribonuclease I/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
4.
Phytomedicine ; 86: 153565, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33945919

RESUMO

BACKGROUND: Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea, nasal itching, and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic, anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied. HYPOTHESIS/PURPOSE: The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism. METHODS: The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs). RESULTS: Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues. Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation, T cell receptor, and the Th17 cell differentiation signaling pathways. Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1, EGFR, c-Jun, NOS2, and JAK2. In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. CONCLUSION: Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.


Assuntos
Alcaloides/farmacologia , Janus Quinase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Rinite Alérgica/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/uso terapêutico , Animais , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Tetra-Hidroisoquinolinas/uso terapêutico
5.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803578

RESUMO

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Cocaína/farmacologia , Condicionamento Clássico , Giro Denteado/metabolismo , Receptores de Dopamina D3/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Derrota Social , Serina-Treonina Quinases TOR/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia
6.
Chem Pharm Bull (Tokyo) ; 69(4): 333-351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790079

RESUMO

A novel series of 7-substituted-2-[3-(2-furyl)acryloyl]-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to clarify structure-activity relationships for peroxisome proliferator-activated receptor γ (PPARγ) partial agonist activity and identify more efficacious PPARγ partial agonists with minor adverse effects. Among the derivatives synthesized, compound 26v with a 2-(2,5-dihydropyrrol-1-yl)-5-methyloxazol-4-ylmethoxy group at the 7-position of the tetrahydroisoquinoline structure exhibited stronger PPARγ agonist and antagonist activities (EC50 = 6 nM and IC50 = 101 nM) than previously reported values for compound 1 (EC50 = 13 nM and IC50 = 512 nM). Compound 26v had very weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and showed higher oral absorption (Cmax = 11.4 µg/mL and area under the curve (AUC) = 134.7 µg·h/mL) than compound 1 (Cmax = 7.0 µg/mL and AUC = 63.9 µg·h/mL) in male Sprague-Dawley (SD) rats. A computational docking calculation revealed that 26v bound to PPARγ in a similar manner to that of compound 1. In male Zucker fatty rats, 26v and pioglitazone at 10 and 30 mg/kg for 4 weeks similarly reduced plasma triglyceride levels, increased plasma adiponectin levels, and attenuated increases in plasma glucose levels in the oral glucose tolerance test, while only pioglitazone decreased hematocrit values. In conclusion, 6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives provide a novel scaffold for selective PPARγ partial agonists and 26v attenuates insulin resistance possibly by adiponectin enhancements with minor adverse effects.


Assuntos
PPAR gama/agonistas , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Técnicas de Química Sintética , Descoberta de Drogas , Humanos , Masculino , Modelos Moleculares , PPAR gama/metabolismo , Ratos Sprague-Dawley , Ratos Zucker , Tetra-Hidroisoquinolinas/síntese química
7.
Biomolecules ; 11(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799860

RESUMO

Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R-/- mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R-/-; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R-/-, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R-/-, whereas SB-277011-A significantly reduced it in WT but did not in D3R-/-. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R-/-. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R-/- and/or in the presence of D3R antagonist is likely to be unrelated to DRs.


Assuntos
Aorta/fisiologia , Receptores de Dopamina D3/metabolismo , Vasoconstrição/genética , Animais , Aorta/efeitos dos fármacos , Indóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrilas/farmacologia , Piperidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/genética , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Vasoconstrição/efeitos dos fármacos
8.
Phytother Res ; 35(7): 3836-3847, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33792976

RESUMO

Melanoma is the most common type of skin cancer. Signal transducer and activator of transcription 3 (STAT3) signaling has been demonstrated to be a therapeutic target for melanoma. Dauricine (Dau), an alkaloid compound isolated from the root of Menispermum dauricum DC., has shown tumor-suppressing effects in multiple human cancers, but its potential in melanoma remains unexplored. In this study, we demonstrated that Dau significantly inhibited the viability and proliferation of A375 and A2058 melanoma cells. Death of melanoma cells was also markedly promoted by Dau. Moreover, Dau inhibited phosphorylation-mediated activation of STAT3 and Src in a dose-dependent manner. Notably, constitutive activation of Src partially abolished the antiproliferative and cytotoxic activities of Dau on melanoma cells. Molecular docking showed that Dau could dock on the kinase domain of Src with a binding energy of -10.42 kcal/mol. Molecular dynamics simulations showed that Src-Dau binding was stable. Surface plasmon resonance imaging analysis also showed that Dau has a strong binding affinity to Src. In addition, Dau suppressed the growth of melanoma cells and downregulated the activation of Src/STAT3 in a xenograft model in vivo. These data demonstrated that Dau inhibits proliferation and promotes cell death in melanoma cells by inhibiting the Src/STAT3 pathways.


Assuntos
Benzilisoquinolinas/farmacologia , Melanoma , Proteínas Proto-Oncogênicas pp60(c-src) , Fator de Transcrição STAT3 , Tetra-Hidroisoquinolinas/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Melanoma/tratamento farmacológico , Simulação de Acoplamento Molecular , Fosforilação , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Bioorg Med Chem Lett ; 42: 128047, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33882273

RESUMO

The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing D3R ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces D3R affinity and negatively impacts selectivity versus D2R for compounds possessing a 6-methoxy-1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, D3R affinity appears to be regulated by the primary pharmacophore group and high affinity D3R ligands with 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline primary pharmacophore groups were identified. The results of this study also indicate that D3R selectivity versus the σ2R is dictated by the benzamide secondary pharmacophore group, this being facilitated with 4-substituted benzamides. Compounds 5s and 5t were identified as high affinity (Ki < 4 nM) D3R ligands. Docking studies revealed that the added phenyl ring moiety interacts with the Cys181 in D3R which partially accounts for the strong D3R affinity of the ligands.


Assuntos
Receptores de Dopamina D3/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Xilenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Xilenos/química
10.
Eur J Med Chem ; 216: 113336, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33725657

RESUMO

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Furanos/metabolismo , Furanos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
11.
Eur J Pharmacol ; 900: 174013, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33766620

RESUMO

RATIONALE: Higenamine (HG), is one of the main active components in many widely used Chinese herbs, and a common ingredient of health products in Europe and North America. Several groups, including our own, have previously shown the beneficial effects of HG against cardiomyocyte death during acute ischemic damage. However, the effect of HG on chronic cardiac remodeling, such as cardiac fibrosis, remains unknown. OBJECTIVE: Herein, we aim to investigate the role of HG in cardiac fibrosis in vivo as well as its cellular and molecular mechanisms. METHODS AND RESULTS: Chronic pressure overload with transverse aortic constriction (TAC) significantly increased cardiac hypertrophy, fibrosis, and cardiac dysfunction in mice, which were significantly attenuated by HG. Consistently, cardiac fibrosis induced by the chronic infusion of isoproterenol (ISO), was also significantly reduced by HG. Interestingly, our results showed that HG had no effect on adult mouse CM hypertrophy in vitro. However, HG suppressed the activation of cardiac fibroblasts (CFs) in vitro. Furthermore, TGF-ß1-induced expression of ACTA2, a marker of fibroblast activation, was significantly suppressed by HG. Concomitantly, HG inhibited TGF-ß1-induced phosphorylation of Smad2/3 in CFs. HG also reduced the expression of extracellular matrix molecules such as collagen I and collagen III. To our surprise, the inhibitory effect of HG on CFs activation was independent of the activation of the beta2 adrenergic receptor (ß2-AR) that is known to mediate the effect of HG on antagonizing CMs apoptosis. CONCLUSION: Our findings suggest that HG ameliorates pathological cardiac fibrosis and dysfunction at least partially by suppressing TGF-ß1/Smad signaling and CFs activation.


Assuntos
Alcaloides/farmacologia , Fibrinolíticos/farmacologia , Fibroblastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Actinas/antagonistas & inibidores , Agonistas Adrenérgicos beta , Animais , Aorta/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Fibrose/prevenção & controle , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Isoproterenol , Camundongos , Ratos , Ratos Sprague-Dawley
12.
Drug Deliv ; 28(1): 580-593, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33729067

RESUMO

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-ß (Aß) protein by GO. Both in vivo and in vitro models were induced using Aß1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aß1-42-induced AD. This proved that GO loaded with Dau could protect against Aß1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Benzilisoquinolinas/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Tetra-Hidroisoquinolinas/farmacologia , Administração Intranasal , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzilisoquinolinas/administração & dosagem , Linhagem Celular , Química Farmacêutica , Modelos Animais de Doenças , Grafite/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/biossíntese , Propriedades de Superfície , Tetra-Hidroisoquinolinas/administração & dosagem
13.
Chem Pharm Bull (Tokyo) ; 69(2): 155-177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518599

RESUMO

The biologically active, naturally occurring 1,2,3,4-tetrahydroisoquinoline-quinone (THIQ) family members isolated from Actinomycetes and marine organisms have been studied thoroughly over the past five decades. Among them, marine natural products along with their reduced compounds, such as renieramycins and ecteinascidins, have attracted interest due to their fantastic structures and meager availability in nature as well as their potent antitumor profiles. As part of our search for new anticancer metabolites through the isolation and characterization of anticancer THIQ compounds from Thai marine animals, we have developed a fascinating THIQ natural product chemistry and medicinal chemistry based on knowledge of the chemistry of saframycin antibiotics as well as their isolation, characterization, transformation, partial synthesis, and total synthesis. This review mainly presents our contributions during 1999-2019 to the field of research on biologically active renieramycin along with ecteinascidin marine natural products.


Assuntos
Actinobacteria/química , Antineoplásicos/química , Organismos Aquáticos/química , Produtos Biológicos/química , Isoquinolinas/química , Actinobacteria/metabolismo , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Organismos Aquáticos/metabolismo , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Isoquinolinas/isolamento & purificação , Isoquinolinas/farmacologia , Conformação Molecular , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/isolamento & purificação , Tetra-Hidroisoquinolinas/farmacologia
14.
Int J Nanomedicine ; 16: 1245-1259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33633449

RESUMO

Purpose: To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed. Methods: Surfactants and solid carriers were screened based on a solubility and a flowability test, respectively. Supersaturating agents, including Poloxamer 407 (P407), were screened. The SSuM was optimized using a Box-Behnken design with three independent variables, including Gelucire 44/14:Brij L4 (G44/BL4; X1) and the amounts of Florite PS-10 (FLO; X2) and Vivapur 105 (VP105; X3), and three response variables, ie, dissolution efficiency at 30 min (Y1), dissolution enhancing capacity (Y2), and Carr's index (Y3). The solid state property was evaluated, and a dissolution test was conducted. RVP, Revanex®, solid micelle (P407-free from the composition of SSuM), and SSuM were orally administrated to rats (RVP 20 mg equivalent/kg) for in vivo pharmacokinetic study. Results: G44 and BL4 showed great solubility, with a critical micelle concentration range of 119.2-333.0 µg/mL. P407 had an excellent supersaturating effect. FLO and VP105 were selected as solid carriers, with a critical solidifying ratio (g/mL) of 0.30 and 0.91, respectively. With optimized values of X1 (-0.41), X2 (0.31), and X3 (-0.78), RVP (200 mg)-containing SSuM consisting of G44 (253.8 mg), BL4 (106.2 mg), FLO (99.3 mg), VP105 (199.8 mg), and P407 (40 mg) was developed, resulting in Y1 (40.3%), Y2 (0.008), and Y3 (12.3%). RVP existed in an amorphous state in the optimized SSuM, and the SSuM formed a nanosized dispersion in the aqueous phase, with approximately 71.7% dissolution at 2 h. The optimized SSuM improved the relative bioavailability of RVP in rats by approximately 478%, 276%, and 161% compared to raw RVP, Revanex®, and solid micelle, respectively. Conclusion: The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.


Assuntos
Micelas , Pirimidinonas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Composição de Medicamentos , Masculino , Modelos Teóricos , Tamanho da Partícula , Polietilenoglicóis , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Soluções , Tensoativos/química , Tetra-Hidroisoquinolinas/farmacocinética
15.
Bioorg Chem ; 109: 104723, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33618250

RESUMO

Natural products are a rich source of lead compounds and have shown promise for epigenetic drug discovery. In this work, we discovered higenamine from our natural product library as a potent, selective and cellular active natural LSD1 inhibitor. Higenamine shows acceptable potency against LSD1 and high selectivity towards LSD1 over MAOA/B. Higenamine significantly increases expression of LSD1 substrates H3K4me1 and H3K4me2 in MLL-rearranged leukemia cells MV4-11 and MOLM-13, but nearly had no effect on LSD1 and H3K4Me3. Meanwhile, higenamine dose-dependently suppresses the levels of HOXA9 and MEIS1 that are overexpressed in leukemia cell lines. Notably, higenamine induces cell differentiation of MV4-11 and MOLM-13 cells accompanying by increased expression of CD11b, CD14 and CD86. Higenamine promotes cell apoptosis, inhibits colony formation, but does not inhibit proliferation of leukemia cells significantly. In addition, the expression levels of p53 are dramatically changed by higenamine in an LSD1-dependent manner in MV4-11 cells. Taken together, higenamine could be employed as a starting point for the development of more selective and potent LSD1 inhibitors. Our work firstly reveals the non-classical epigenetic regulation mechanism of higenamine in cancers, and also demonstrates the efficacy of higenamine for MLL-rearranged leukemia therapy.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Histona Desmetilases/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Leucemia/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/genética , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química
16.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513818

RESUMO

In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-ß (Aß). The purpose of this study was to investigate the effect of pharmacological inhibition of Aß efflux transporters on BBB function and Aß accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/administração & dosagem , Doença de Alzheimer/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Imunoglobulina G/metabolismo , Imuno-Histoquímica , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Junções Íntimas/metabolismo
17.
Pharmacol Rep ; 73(2): 490-505, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33403530

RESUMO

BACKGROUND: The aim of the present study was to evaluate the effect of 1MeTIQ on fear memory and social interaction in an MK-801-induced model of schizophrenia. The results obtained after administration of 1MeTIQ were compared with those obtained with olanzapine, an antipsychotic drug. METHODS: Sprague-Dawley rats received a single injection of MK-801 to induce behavioral disorders. 1MeTIQ was given either acutely in a single dose or chronically for 7 consecutive days. Olanzapine was administered once. In groups receiving combined treatments, 1MeTIQ or olanzapine was administered 20 min before MK-801 injection. Contextual fear conditioning was used to assess disturbances in fear memory (FM), and the sociability of the rats was measured in the social interaction test (SIT). Biochemical analysis was carried out to evaluate monoamine levels in selected brain structures after treatment. RESULTS: Our results are focused mainly on data obtained from neurochemical studies, demonstrating that 1MeTIQ inhibited the MK-801-induced reduction in dopamine levels in the frontal cortex and increased the 5-HT concentration. The behavioral tests revealed that acute administration of MK-801 caused disturbances in both the FM and SIT tests, while neither 1MeTIQ nor olanzapine reversed these deficits. CONCLUSION: 1MeTIQ, although pharmacologically effective (i.e., it reverses MK-801-induced changes in monoamine activity), did not influence MK-801-induced social and cognitive deficits. Thus, our FM tests and SIT did not support the main pharmacological hypotheses that focus on dopamine system stabilization and dopamine-serotonin system interactions as probable mechanisms for inhibiting the negative symptoms of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Olanzapina/farmacologia , Esquizofrenia/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Interação Social , Tetra-Hidroisoquinolinas/administração & dosagem
18.
Eur J Med Chem ; 211: 113004, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33218684

RESUMO

Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Psoríase/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
19.
Eur J Med Chem ; 209: 112906, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049607

RESUMO

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.


Assuntos
Proteínas de Membrana/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Receptores sigma/antagonistas & inibidores , Tetra-Hidroisoquinolinas/química , Cálcio/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Células MCF-7 , Fármacos Neuroprotetores/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacologia
20.
Eur J Med Chem ; 210: 113092, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333398

RESUMO

Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.


Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estrutura Molecular , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
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