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1.
J Immunother ; 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38557756

RESUMO

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

3.
Chem Biol Drug Des ; 103(1): e14376, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37852922

RESUMO

Ribosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB-1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA-MB-468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU-74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA-MB-468 cell anti-proliferation activity (IC50 = 0.13 µM). The in vivo tumor growth inhibitory activities were evaluated with compounds B1-B3 in MDA-MB-468 xenograft model which gave up to 54.6% of TGI.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Relação Estrutura-Atividade , Piridinas/química , Proliferação de Células , Sulfonamidas/farmacologia , Anticonvulsivantes/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Estrutura Molecular , Inibidores de Proteínas Quinases/química
4.
J Med Chem ; 67(1): 479-491, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38110353

RESUMO

The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.


Assuntos
Antineoplásicos , Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Platina , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Catálise , Linhagem Celular Tumoral
5.
Med Res Rev ; 44(3): 975-1012, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38126568

RESUMO

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/tratamento farmacológico , AVC Isquêmico/etiologia , Terapia Trombolítica/efeitos adversos , Trombectomia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Resultado do Tratamento
6.
J Med Chem ; 66(24): 16680-16693, 2023 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-38069814

RESUMO

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.


Assuntos
Equinococose , Echinococcus granulosus , Camundongos , Animais , Harmina/farmacologia , Harmina/uso terapêutico , Equinococose/tratamento farmacológico , Echinococcus granulosus/ultraestrutura , Albendazol/farmacocinética , Albendazol/uso terapêutico
7.
Eur J Med Chem ; 262: 115912, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37931330

RESUMO

Ischemic stroke (IS) is a life-threatening disease worldwide. Nitric oxide (NO) derived from l-arginine catalyzed by NO synthase (NOS) is closely associated with IS. Three isomers of NOS (nNOS, eNOS and iNOS) produce different concentrations of NO, resulting in quite unlike effects during IS. Of them, n/iNOSs generate high levels of NO, detrimental to brain by causing nerve cell apoptosis and/or necrosis, whereas eNOS releases small amounts of NO, beneficial to the brain via increasing cerebral blood flow and improving nerve function. As a result, a large variety of NO regulators (NO donors or n/iNOS inhibitors) have been developed for fighting IS. Regrettably, up to now, no review systematically introduces the progresses in this area. This article first outlines dynamic variation rule of NOS/NO in IS, subsequently highlights advances in NO regulators against IS, and finally presents perspectives based on concentration-, site- and timing-effects of NO production to promote this field forward.


Assuntos
AVC Isquêmico , Óxido Nítrico , Humanos , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Arginina
8.
J Med Chem ; 66(20): 14221-14240, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37820326

RESUMO

Invasive fungal infections (IFIs) such as cryptococcal meningitis (CM) remain a serious health issue worldwide due to drug resistance closely related to biofilm formation. Unfortunately, available antifungal drugs with ideal safety and promising potency are still lacking; thus, the research of new candidate and therapeutic approach is urgently needed. As an important gas messenger molecule, nitric oxide (NO) shows vital inhibition on various microorganism biofilms. Hence, three series of novel NO-donating azole derivatives were designed and synthesized, and the in vitro antifungal activity as well as the mechanism of action was investigated. Among them, 3a and 3e displayed excellent antifungal activity against Cryptococcus neoformans and biofilm depending on the release of NO. Moreover, a more stable analogue 3h of 3a demonstrated markedly anti-CM effects via intranasal dropping, avoiding the first-pass effects and possessing a better brain permeability bypass blood-brain barrier. These results present a promising antifungal candidate and intranasal dropping approach for the treatment of CM, warranting further studies.


Assuntos
Criptococose , Cryptococcus neoformans , Meningite Criptocócica , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Azóis/farmacologia , Criptococose/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Testes de Sensibilidade Microbiana
9.
J Photochem Photobiol B ; 248: 112798, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37820499

RESUMO

BACKGROUND: Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with PDT will greatly limit its effects. As a hypoxic-activated pre-chemotherapeutic drug, tirapazamine (TPZ) can be only activated and produce cytotoxicity under hypoxia environment. Albendazole sulfoxide (ABZSO) is the first choice for the treatment of Egs. This study aimed to explore the effects of ABZSO nanoparticles (ABZSO NPs), TPZ combined with PDT on the activity of Egs in vitro and in vivo. METHODS: The Egs were divided into control, ABZSO NPs, ABZSO NPs + PDT, and ABZSO NPs + TPZ + PDT groups, and the viability of Egs was determined using methylene blue staining. Then, the ROS, LDH and ATP levels were measured using their corresponding assay kit, and H2AX and TopoI protein expression was detected by western blot. The morphology of Egs with different treatments was observed using hematoxylin eosin (HE) staining and scanning electron microscopy (SEM). After that, the in vivo efficacy of ABZSO NPs, TPZ and PDT on Egs was determined in a Egs infected mouse model. RESULTS: In vitro experiments showed that the combined treatment of TPZ, ABZSO NPs and PDT significantly inhibited Egs viability; and significantly increased ROS levels and LDH contents, while decreased ATP contents in Egs; as well as up-regulated H2AX and down-regulated TopoI protein expression. HE staining and SEM results showed that breaking-then-curing treatment seriously damaged the Egs wall. Additionally, in vivo experiments found that the combination of ABZSO NPs, PDT and TPZ had more serious calcification and damage of the wall structure of cysts. CONCLUSIONS: ABZSO NPs combined with TPZ and PDT has a better inhibitory effect on the growth of Egs in vitro and in vivo based on the strategy of "breaking-then-curing".


Assuntos
Equinococose , Echinococcus granulosus , Nanopartículas , Fotoquimioterapia , Animais , Camundongos , Tirapazamina/farmacologia , Tirapazamina/química , Tirapazamina/uso terapêutico , Echinococcus granulosus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Hipóxia , Fotoquimioterapia/métodos , Equinococose/tratamento farmacológico , Nanopartículas/química , Trifosfato de Adenosina
10.
ACS Chem Neurosci ; 14(20): 3839-3854, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37768739

RESUMO

Ischemic stroke is a deleterious cerebrovascular disease with few therapeutic options, and its functional recovery is highly associated with the integrity of the blood-brain barrier and neuroinflammation. The Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor fasudil (F) and the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) have been demonstrated to exhibit neuroprotection in a series of neurological disorders. Hence, we synthesized and biologically examined the new salt fasudil dichloroacetate (FDCA) and validated that FDCA was eligible for attenuating ischemic volume and neurological deficits in the rat transient middle cerebral artery occlusion (tMCAO) model. Additionally, FDCA exerted superior effects than fasudil and dichloroacetate alone or in combination in reducing cerebral ischemic injury. Particularly, FDCA could maintain the blood-brain barrier (BBB) integrity by inhibiting matrix metalloproteinase 9 (MMP-9) protein expression and the degradation of zonula occludens (ZO-1) and Occludin protein. Meanwhile, FDCA could mitigate the neuroinflammation induced by microglia. The in vivo and in vitro experiments further demonstrated that FDCA disrupted the phosphorylations of myosin phosphatase target subunit 1 (MYPT1), mitogen-activated protein kinase (MAPK) cascade, including p38 and c-Jun N-terminal kinase (JNK), and pyruvate dehydrogenase (PDH) and limited excessive lactic acid metabolites, resulting in inhibition of BBB disruption and neuroinflammation. In addition, FDCA potently mitigated inflammatory response in human monocytes isolated from ischemic stroke patients, which provides the possibilities of a clinical translation perspective. Overall, these findings provided a therapeutic potential for FDCA as a candidate agent for ischemic stroke and other neurological diseases associated with BBB disruption and neuroinflammation.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Doenças do Sistema Nervoso , Acidente Vascular Cerebral , Ratos , Humanos , Animais , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Doenças Neuroinflamatórias , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo
11.
Chem Biol Drug Des ; 102(2): 395-407, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37062588

RESUMO

The decrease in angiogenesis that occurs with aging significantly contributes to the higher incidence and mortality of cardiovascular diseases among the elderly. This decline in angiogenesis becomes more pronounced with increasing age and is closely linked to abnormal function and senescence of endothelial cells. Enhancing angiogenesis in aging and targeting senescent endothelial cells have gained considerable attention. Nitric oxide (NO) has been thoroughly investigated for its function in regulating angiogenesis and is an important factor that can counteract endothelial cell senescence. This review summarizes the mechanisms of reduced angiogenesis during aging and therapeutic strategies targeting senescent cells. We also discuss the potential of combining the current approaches with NO in promoting angiogenesis in aging vessels.


Assuntos
Células Endoteliais , Óxido Nítrico , Humanos , Idoso , Endotélio Vascular , Envelhecimento , Senescência Celular/fisiologia
12.
Transl Stroke Res ; 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36577854

RESUMO

Cerebral ischemic stroke causes substantial white matter injury, which is further aggravated by neuroinflammation mediated by microglia/astrocytes. Given the anti-neuroinflammatory action of telmisartan and the enhancing blood-brain barrier (BBB) permeability potential of resuscitation-inducing aromatic herbs, 13 hybrids (3a-m) of telmisartan (or its simplified analogues) with resuscitation-inducing aromatic agents were designed, synthesized, and biologically evaluated. Among them, the optimal compound 3a (the ester hybrid of telmisartan and (+)-borneol) potently inhibited neuroinflammation mediated by microglia/astrocytes and ameliorated ischemic stroke. Particularly, 3a significantly conferred protection for white matter integrity after cerebral ischemic stroke via decreasing abnormally dephosphorylated neurofilament protein, upregulating myelin basic protein, and attenuating oligodendrocyte damage. Further RNA-sequencing data revealed that 3a upregulated expression of transcriptional regulator ATF3 to reduce the expression of CH25H, prevented proinflammatory state of lipid-droplet-accumulating microglia/astrocytes to limit excessive inflammation, and eventually protected neighboring oligodendrocytes to prevent white matter injury. Taken with the desirable pharmacokinetics behavior and improved brain distribution, 3a may be a feasible therapeutic agent for ischemic stroke and other neurological disorders with white matter injury.

13.
JACS Au ; 2(10): 2339-2351, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36311834

RESUMO

Bio-orthogonal bond-cleavage reactions have been used in cancer therapy for improving the biological specificity of prodrug activation, but the spatiotemporal consistency of reactants is still a huge challenge. Although, in most cases, the cleavage catalysts and caged prodrugs are administrated separately, it is difficult to avoid the reactions in advance before they meet at the tumor site. Herein, we design and construct novel coordinative nanoparticles, integrating two prodrugs A and B as ligands and ferric ions as coordinative centers. After nanoparticles accumulated in tumor through passive targeting, inert Pt(IV) prodrug A is specifically and spontaneously reduced into active Pt(II) cisplatin, which acts as the cleavage catalyst to subsequently initiate the in situ bio-orthogonal depropargylation of B, that is, O 2-propargyl nitric oxide (NO) donor. The unique structure of coordinative nanoparticles ensures the spatiotemporal consistency of reactants (prodrugs A and B) and products (cytotoxic cisplatin and tumoricidal NO) for the bio-orthogonal bond-cleavage reaction, which leads to an improved synergistic therapeutic activity for triple-negative breast cancer (TNBC). This new concept of bio-orthogonal dual-prodrug coordinative nanoparticles may inspire further applications in bio-orthogonal chemistry and drug delivery for combination chemotherapy.

14.
J Med Chem ; 65(17): 11745-11758, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36007247

RESUMO

Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives RNO-1-RNO-6 was designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound RNO-6 maintained potent ROCK inhibitory and NO releasing abilities, reversibly depolymerized F-actin, and suppressed mitochondrial respiration in human trabecular meshwork (HTM) cells. Topical administration of RNO-6 (0.26%) in chronic ocular hypertension glaucoma mice exhibited significant IOP lowering and visual function and retinal ganglion cell (RGC) protection activities, superior to an equal molar dose of ripasudil. RNO-6 could be a promising agent for glaucoma or ocular hypertension, warranting further investigation.


Assuntos
Glaucoma , Hipertensão Ocular , Animais , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular , Isoquinolinas , Camundongos , Óxido Nítrico , Hipertensão Ocular/tratamento farmacológico , Células Ganglionares da Retina , Sulfonamidas , Quinases Associadas a rho
15.
Bioorg Med Chem ; 69: 116891, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35764031

RESUMO

The treatment of acute ischemic stroke (AIS) remains a tough challenge in clinic. Here, we report the anti-AIS activity of R- and S-FMPB generated from hybridization of ring-opened R- and S-3-N-butylphthalide (R- and S-NBP) derivatives (R- and S-APB) with 4-fluro-edaravone (4-F-Eda), respectively. S-FMPB (10 mg/kg, iv) significantly improved the neurological score and alleviated cerebral infarction and edema of rats suffered from transient middle cerebral artery occlusion (tMCAO), superior to RS- and R-FMPB, as well as better than RS-FMPB by oral administration in previous studies. Importantly, S-FMPB is more active not only than the equimolar S-APB and 4-F-Eda alone or in combination but also than the clinical drugs NBP and edaravone (Eda) in combination at the equimolar doses. Furthermore, S-FMPB showed relative stability in plasma or liver microsome of rats but could be converted into two active metabolites (S-NBP and 4-F-Eda) in rats with good pharmacokinetic properties in terms of longer half-life period (t1/2) and mean residence time (MRT) as well as larger area under the concentration-time curve (AUC) of S-NBP than those from S-NBP and 4-F-Eda single or in combination by iv administration, suggesting that S-NBP and 4-F-Eda may synergistically play the anti-AIS activity. Our findings suggest that S-FMPB may be used as a potential anti-AIS agent to further study.


Assuntos
Benzofuranos , AVC Isquêmico , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Edaravone/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Acidente Vascular Cerebral/tratamento farmacológico
16.
J Med Chem ; 65(8): 5902-5925, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35412827

RESUMO

Protein S-nitrosation (SNO), a posttranslational modification (PTM) of cysteine (Cys) residues elicited by nitric oxide (NO), regulates a wide range of protein functions. As a crucial form of redox-based signaling by NO, SNO contributes significantly to the modulation of physiological functions, and SNO imbalance is closely linked to pathophysiological processes. Site-specific identification of the SNO protein is critical for understanding the underlying molecular mechanisms of protein function regulation. Although careful verification is needed, SNO modification data containing numerous functional proteins are a potential research direction for druggable target identification and drug discovery. Undoubtedly, SNO-related research is meaningful not only for the development of NO donor drugs but also for classic target-based drug design. Herein, we provide a comprehensive summary of SNO, including its origin and transport, identification, function, and potential contribution to drug discovery. Importantly, we propose new views to develop novel therapies based on potential protein SNO-sourced targets.


Assuntos
Cisteína , Proteína S , Cisteína/química , Óxido Nítrico/metabolismo , Nitrosação , Processamento de Proteína Pós-Traducional , Proteína S/metabolismo , Proteínas/metabolismo
17.
Acta Pharm Sin B ; 11(7): 1867-1884, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34386325

RESUMO

Blood-brain barrier (BBB) damage after ischemia significantly influences stroke outcome. Compound LFHP-1c was previously discovered with neuroprotective role in stroke model, but its mechanism of action on protection of BBB disruption after stroke remains unknown. Here, we show that LFHP-1c, as a direct PGAM5 inhibitor, prevented BBB disruption after transient middle cerebral artery occlusion (tMCAO) in rats. Mechanistically, LFHP-1c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity, but also reduced the interaction of PGAM5 with NRF2, which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia. Furthermore, LFHP-1c administration by targeting PGAM5 shows a trend toward reduced infarct volume, brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with tMCAO. Thus, our study identifies compound LFHP-1c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo, and provides a potentially therapeutics for brain ischemic stroke.

18.
Chin J Nat Med ; 19(7): 545-550, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247779

RESUMO

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.


Assuntos
Colite , Mesalamina/farmacologia , Ácido Oleanólico/análogos & derivados , Pró-Fármacos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Camundongos , Nitrorredutases , Ácido Oleanólico/farmacologia
19.
Curr Top Med Chem ; 21(24): 2213-2229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34218787

RESUMO

Biofilms are among the most important causes of nosocomial and recurrent infections as biofilms confer antibiotic resistance to pathogenic bacteria and protect them from the host's immune system. Thus, it is imperative to investigate effective therapeutic agents to counteract biofilms. As an important signaling molecule, Nitric Oxide (NO) plays a crucial role in various biological and pathological processes. NO could disperse biofilm and restore the drug sensitivity by reducing intracellular cyclic-diguanosine monophosphate (c-di-GMP) levels. This review highlights recent advances on antibacterial and antibiofilm effects of NO when NO was co-administered with other antimicrobial agents. A significant improvement in drug permeability and biofilm cell targeting and reduced cytotoxicity could be attained with this strategy. In this review, we briefly lay out challenges and propose future directions in this appealing avenue of research on NO-based therapy for biofilm eradication.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Óxido Nítrico/farmacologia , Animais , Antibacterianos/uso terapêutico , Humanos , Óxido Nítrico/uso terapêutico
20.
J Med Chem ; 64(15): 10919-10933, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34292749

RESUMO

The treatment of ischemic stroke (IS) remains a big challenge in clinics, and it is urgently needed to develop novel, safe, and effective medicines against IS. Here, we report the design, synthesis, and biological evaluation of organic NO2- donors as potential agents for the treatment of IS. The representative compound 4a was able to slowly generate low concentrations of NO2- by reaction with a thiol-containing nucleophile, and the NO2- was selectively converted into NO under ischemic/hypoxia conditions to protect primary rat neurons from oxygen-glucose deprivation and recovery (OGD/R)-induced cytotoxicity by enhancing the Nrf2 signaling and activating the NO/cGMP/PKG pathway. Treatment with 4a at 2 h before or after ischemia mitigated the ischemia/reperfusion-induced brain injury in middle cerebral artery occlusion (MCAO) rats by producing NO and enhancing Nrf2 signaling. Furthermore, 4a significantly promoted endothelial cell proliferation and angiogenesis within the ischemic penumbra. Our findings suggest that this type of NO2- donors, like 4a, may be valuable to fight IS and other ischemic diseases.


Assuntos
Desenho de Fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nitritos/farmacologia , Animais , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Nitritos/síntese química , Nitritos/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
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