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1.
Proteins ; 92(8): 959-974, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38602129

RESUMO

Peptides are promising therapeutic agents for various biological targets due to their high efficacy and low toxicity, and the design of peptide ligands with high binding affinity to the target of interest is of utmost importance in peptide-based drug design. Introducing a conformational constraint to a flexible peptide ligand using a side-chain lactam-bridge is a convenient and efficient method to improve its binding affinity to the target. However, in general, such a small structural modification to a flexible ligand made with the intent of lowering the configurational entropic penalty for binding may have unintended consequences in different components of the binding enthalpy and entropy, including the configurational entropy component, which are still not clearly understood. Toward probing this, we examine different components of the binding enthalpy and entropy as well as the underlying structure and dynamics, for a side-chain lactam-bridged peptide inhibitor and its flexible analog forming complexes with vascular endothelial growth factor (VEGF), using all-atom molecular dynamics simulations. It is found that introducing a side-chain lactam-bridge constraint into the flexible peptide analog led to a gain in configurational entropy change but losses in solvation entropy, solute internal energy, and solvation energy changes upon binding, pinpointing the opportunities and challenges in drug design. The present study features an interplay between configurational and solvation entropy changes, as well as the one between binding enthalpy and entropy, in ligand-target binding upon imposing a conformational constraint into a flexible ligand.


Assuntos
Inibidores da Angiogênese , Entropia , Lactamas , Simulação de Dinâmica Molecular , Ligação Proteica , Termodinâmica , Fator A de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Lactamas/química , Lactamas/metabolismo , Ligantes , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Humanos , Peptídeos/química , Peptídeos/metabolismo , Sítios de Ligação
2.
Cell Physiol Biochem ; 58(1): 63-82, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374715

RESUMO

BACKGROUND/AIMS: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear. METHODS: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs. RESULTS: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>. CONCLUSION: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.


Assuntos
Células Endoteliais , Desiminases de Arginina em Proteínas , Proteínas Proto-Oncogênicas c-akt , Humanos , Células Endoteliais/metabolismo , Histonas/metabolismo , Desiminases de Arginina em Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Amidinas/química , Amidinas/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia
3.
Bioorg Med Chem Lett ; 110: 129858, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38917956

RESUMO

Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination of the phthalimide moiety of immunomodulatory drugs (IMiDs) has a strong beneficial effect on the ability to inhibit angiogenesis. The neomorphic activity of E3 ligase complexes is induced by the binding of IMiDs to cereblon. We investigated that a set of eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce the degradation of neomorphic substrates (IKZF3, GSPT1, CK1α, SALL4). Hence, the antiangiogenic activity of fluorinated IMiDs was not triggered by neosubstrate degradation features. A fluorine scanning of non-traditional IMiDs of the benzamido glutarimide chemotype was performed. By measuring the endothelial cell tube formation, no angiogenesis inhibitors were identified, confirming the narrow structure-activity window of IMiD-induced antiangiogenesis.


Assuntos
Inibidores da Angiogênese , Talidomida , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Talidomida/farmacologia , Talidomida/química , Talidomida/análogos & derivados , Talidomida/síntese química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Halogenação , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
4.
Bioorg Med Chem ; 111: 117866, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39096785

RESUMO

The inhibition of angiogenesis has been considered as an attractive method for the discovery of potential anti-cancer drugs. Herein, we report our new synthesized bibenzyl compound Ae had potent anti-angiogenic activity(the lowest effective concentration is to 0.62-1.25 µM) in zebrafish in vivo and showed a concentration-dependent inhibition of inter-segmental blood vessels (ISVs) compared to control. Further, Ae exhibited the obvious inhibitory activity of proliferation, migration, invasion and tube formation in HUVEC cells in vitro. Moreover, qRT-PCR analysis revealed that the anti-angiogenic activity of compound Ae is connected with the ang-2, tek in ANGPT-TEK pathway and the kdr, kdrl signaling axle in VEGF-VEGFR pathway. Molecular docking studies revealed that compound Ae had an interaction with the angiopoietin-2 receptor(TEK) and VEGFR2. Additionally, analysis of the ADMET prediction data indicated that compound Ae possessed favorable physicochemical properties, drug-likeness, and synthetic accessibility. In conclusion, compound Ae had remarkable anti-angiogenic activity and could be served as an candidate for cancer therapy.


Assuntos
Inibidores da Angiogênese , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana , Simulação de Acoplamento Molecular , Peixe-Zebra , Animais , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Bibenzilas/farmacologia , Bibenzilas/química , Bibenzilas/síntese química , Relação Estrutura-Atividade , Movimento Celular/efeitos dos fármacos , Estrutura Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Relação Dose-Resposta a Droga , Receptor TIE-2/metabolismo , Receptor TIE-2/antagonistas & inibidores
5.
Bioorg Chem ; 148: 107411, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38733747

RESUMO

In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site.


Assuntos
Inibidores da Angiogênese , Antineoplásicos , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Relação Dose-Resposta a Droga , Piridazinas/farmacologia , Piridazinas/química , Piridazinas/síntese química , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos
6.
Bioorg Chem ; 151: 107679, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39094510

RESUMO

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.


Assuntos
Inibidores da Angiogênese , Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Tubulina , Tubulina (Proteína) , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tubulina (Proteína)/metabolismo , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química , Apoptose/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Descoberta de Drogas , Animais , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Camundongos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
7.
Bioorg Chem ; 147: 107358, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38626490

RESUMO

VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.


Assuntos
Inibidores da Angiogênese , Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Tiofenos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Tiofenos/farmacologia , Tiofenos/química , Tiofenos/síntese química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Descoberta de Drogas , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral
8.
Bioorg Chem ; 147: 107405, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38696843

RESUMO

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.


Assuntos
Degeneração Macular , Peptídeos Cíclicos , Receptores CCR3 , Animais , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Degeneração Macular/tratamento farmacológico , Degeneração Macular/patologia , Camundongos , Receptores CCR3/antagonistas & inibidores , Receptores CCR3/metabolismo , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Estrutura Molecular , Relação Estrutura-Atividade , Camundongos Endogâmicos C57BL , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/patologia , Neovascularização de Coroide/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , Angiogênese
9.
Environ Res ; 256: 119180, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38795948

RESUMO

The main focus of anticancer drug discovery is on developing medications that are gentle on normal cells and should have the ability to target multiple anti-cancer pathways. Liver cancer is becoming a worldwide epidemic due to the highest occurring and reoccurring rate in some countries. Calotropis procera is a xerophytic herbal plant growing wildly in Saudi Arabia. Due to its anti-angiogenic and anticancer capabilities, "C. procera" is a viable option for developing innovative anticancer medicines. However, no study has been done previously, to discover angiogenic and anti-cancer targets which are regulated by C. procera in liver cancer. In this study, leaves, stems, flowers, and seeds of C. procera were used to prepare crude extracts and were fractionated into four solvents of diverse polarities. These bioactivity-guided solvent fractions helped to identify useful compounds with minimal side effects. The phytoconstituents present in the leaves and stem were identified by GC-MS. In silico studies were done to predict the anti-cancer targets by major bioactive constituents present in leaves and stem extracts. A human angiogenesis antibody array was performed to profile novel angiogenic targets. The results from this study showed that C. procera extracts are an ideal anti-cancer remedy with minimum toxicity to normal cells as revealed by zebrafish in vivo toxicity screening assays. The novel antiangiogenic and anticancer targets identified in this study could be explored to design medication against liver cancer.


Assuntos
Calotropis , Neoplasias Hepáticas , Extratos Vegetais , Peixe-Zebra , Calotropis/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Neoplasias Hepáticas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Folhas de Planta/química , Feminino , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Simulação por Computador , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/análise , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/análise
10.
J Nanobiotechnology ; 22(1): 290, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802884

RESUMO

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.


Assuntos
Córnea , Neovascularização da Córnea , Nanopartículas , Soluções Oftálmicas , Neovascularização da Córnea/tratamento farmacológico , Animais , Nanopartículas/química , Soluções Oftálmicas/química , Córnea/metabolismo , Córnea/efeitos dos fármacos , Camundongos , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Tamanho da Partícula , Humanos , Masculino , Camundongos Endogâmicos C57BL , Coelhos
11.
J Nanobiotechnology ; 22(1): 375, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926721

RESUMO

As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3'-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer.


Assuntos
Carcinoma Hepatocelular , Cobre , Neoplasias Hepáticas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Cobre/química , Cobre/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Fotoquimioterapia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Porfirinas/química , Porfirinas/farmacologia , Clorofilídeos , Glutationa/metabolismo , Nanopartículas/química , Catálise , Nanopartículas Metálicas/química , Liberação Controlada de Fármacos , Camundongos Nus , Antineoplásicos/farmacologia , Antineoplásicos/química
12.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34006633

RESUMO

Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Proteoglicanas de Heparan Sulfato/farmacologia , Degeneração Macular/tratamento farmacológico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Inibidores da Angiogênese/química , Animais , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/genética , Neovascularização de Coroide/patologia , Cristalografia por Raios X , Células Endoteliais/efeitos dos fármacos , Olho/efeitos dos fármacos , Olho/patologia , Proteoglicanas de Heparan Sulfato/genética , Proteoglicanas de Heparan Sulfato/imunologia , Heparina/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/ultraestrutura , Injeções Intravítreas , Degeneração Macular/genética , Degeneração Macular/patologia , Camundongos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/ultraestrutura , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Corpo Vítreo/efeitos dos fármacos
13.
Arch Pharm (Weinheim) ; 357(10): e2400411, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39008876

RESUMO

The vascular endothelial growth factor receptor (VEGFR) is a receptor tyrosine kinase that is regarded as an emerging target for abnormal angiogenesis diseases. In this study, novel naphthalene imidazo[1,2-b]pyridazine hybrids as VEGFR selective inhibitors were designed and synthesized using a scaffold hopping strategy based on ponatinib, a multitarget kinase inhibitor. Among the evaluated compounds, derivative 9k (WS-011) demonstrated the most potent inhibitory potency against VEGFR-2 (IC50 = 8.4 nM) and displayed superior VEGFR selectivity over a panel of 70 kinases compared with ponatinib. Furthermore, 9k possessed good cytotoxic effects on various cancer cell lines, especially the colon cancer HT-29 cells, with an acceptable oral bioavailability. Moreover, 9k significantly inhibited the migration and invasion of human umbilical vein endothelial cells (HUVEC) cells and induced apoptosis through the upregulation of apoptotic proteins in HT-29 cells. 9k also effectively suppressed the activation of VEGFR-2 signaling pathways, which in turn inhibited the growth of HT-29 cells and the tube formation of HUVECs in vitro. All of the findings revealed that 9k could be considered a promising antiangiogenesis lead that merits further investigation.


Assuntos
Apoptose , Desenho de Fármacos , Células Endoteliais da Veia Umbilical Humana , Naftalenos , Inibidores de Proteínas Quinases , Piridazinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Piridazinas/farmacologia , Piridazinas/síntese química , Piridazinas/química , Naftalenos/farmacologia , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células HT29 , Apoptose/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Imidazóis/síntese química , Imidazóis/química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Bioorg Chem ; 141: 106873, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37734192

RESUMO

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.


Assuntos
Alcaloides , Melanoma , Camundongos , Animais , Humanos , Peixe-Zebra , Neovascularização Patológica/patologia , Camundongos Endogâmicos C57BL , Células Endoteliais da Veia Umbilical Humana , Inibidores da Angiogênese/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Melanoma/tratamento farmacológico , Proliferação de Células
15.
J Biochem Mol Toxicol ; 36(2): e22954, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34783123

RESUMO

Marine resources are notably explored for their unique biomolecules that have been designed to be drug targets for their immense potential against various pathologies. These biomolecules are mostly secondary metabolites from different species that include sponges, tunicates, echinoderms, ascidians, algae, and marine symbionts. Among the various biological activities of the marine biomolecules, antiangiogenic property has gained much significance in alternate therapy for treatment against cancer. Hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) are the prime signaling pathways related to angiogenesis that are exclusively designated as markers for critical selection of novel inhibitors. This is mainly due to their importance in tumor induction and regulatory control over other interlinked pathways involved in cancer. Small molecular drug screening using the zebrafish model has been an advantage in cancer research in recent times. This review addresses the importance of marine biomolecules and their antiangiogenic efficacy by targeting HIF/VEGF pathways experimented in the zebrafish model in the last decade. Thus, it would provide more clear insights into the role of biomolecules in alternative cancer therapy.


Assuntos
Inibidores da Angiogênese , Organismos Aquáticos/química , Endotélio Vascular/metabolismo , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas de Peixe-Zebra/antagonistas & inibidores , Peixe-Zebra/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo
16.
J Nanobiotechnology ; 20(1): 7, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983556

RESUMO

BACKGROUND: Inhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious. An antagonist peptide of VEGFA/VEGFB, referred to as VGB3, can recognize and neutralize both VEGFR1 and VEGFR2 on the endothelial and tumoral cells, thereby inhibits angiogenesis and tumor growth. However, improved efficacy and extending injection intervals is required for its clinical translation. Given that gold nanoparticles (GNPs) can enhance the efficacy of biotherapeutics, we conjugated VGB3 to GNPs to enhance its efficacy and extends the intervals between treatments without adverse effects. RESULTS: GNP-VGB3 bound to VEGFR1 and VEGFR2 in human umbilical vein endothelial (HUVE) and 4T1 mammary carcinoma cells. GNP-VGB3 induced cell cycle arrest, ROS overproduction and apoptosis and inhibited proliferation and migration of endothelial and tumor cells more effectively than unconjugated VGB3 or GNP. In a murine 4T1 mammary carcinoma tumor model, GNP-VGB3 more strongly than VGB3 and GNP inhibited tumor growth and metastasis, and increased animal survival without causing weight loss. The superior antitumor effects were associated with durable targeting of VEGFR1 and VEGFR2, thereby inhibiting signaling pathways of proliferation, migration, differentiation, epithelial-to-mesenchymal transition, and survival in tumor tissues. MicroCT imaging and inductively coupled plasma mass spectrometry showed that GNP-VGB3 specifically target tumors and exhibit greater accumulation within tumors than the free GNPs. CONCLUSION: Conjugation to GNPs not only improved the efficacy of VGB3 peptide but also extended the intervals between treatments without adverse effects. These results suggest that GNP-VGB3 is a promising candidate for clinical translation.


Assuntos
Inibidores da Angiogênese , Ouro/química , Nanopartículas Metálicas/química , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
J Enzyme Inhib Med Chem ; 37(1): 652-665, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35109719

RESUMO

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Colchicina/antagonistas & inibidores , Indóis/farmacologia , Neovascularização Patológica/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Peixe-Zebra
18.
J Enzyme Inhib Med Chem ; 37(1): 339-354, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34979843

RESUMO

α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone 4c demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC50 values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that 4c could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that 4c arrested MGC-803 cell cycle at G2/M phase. In addition, 4c dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound 4c was found to inhibit the HUVECs tube formation, migration, and invasion in vitro. Furthermore, our data suggested that treatment with 4c significantly reduced MGC-803 cells metastasis and proliferation in vitro. Overall, this work showed that chalcone hybrid 4c is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Chalconas/farmacologia , Colchicina/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Halogenação , Humanos , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
19.
Int J Mol Sci ; 23(3)2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35162998

RESUMO

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.


Assuntos
Organismos Aquáticos/química , Esteroides/química , Esteroides/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Colestanos/química , Colestanóis/química , Humanos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Espermina/análogos & derivados , Espermina/química , Esteroides/síntese química , Triterpenos/síntese química
20.
Molecules ; 27(15)2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35897938

RESUMO

Antiangiogenic agents attenuate tumours' growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40-55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25-37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4-C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target's binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.


Assuntos
Antineoplásicos , Flavonas , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células , Células Endoteliais/metabolismo , Flavonas/química , Flavonas/farmacologia , Flavonoides/farmacologia , Fosforilação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
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