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1.
Drug Deliv ; 29(1): 1243-1256, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35416106

RESUMO

The present study aimed to evaluate the anti-tumor efficacy of the epidermal growth factor receptor (EGFR)-targeting recombinant fusion protein Fv-LDP-D3 and its antibody-drug conjugate Fv-LDP-D3-AE against esophageal cancer. Fv-LDP-D3, consisting of the fragment variable (Fv) of an anti-EGFR antibody, the apoprotein of lidamycin (LDP), and the third domain of human serum albumin (D3), exhibited a high binding affinity for EGFR-overexpressing esophageal cancer cells, inhibited EGFR phosphorylation and down-regulated inosine monophosphate dehydrogenase type II (IMPDH2) expression. Fv-LDP-D3 was taken up by cancer cells through intensive macropinocytosis; it inhibited the proliferation and induced the apoptosis of esophageal cancer cells. In vivo imaging revealed that Fv-LDP-D3 displayed specific tumor-site accumulation and a long-lasting retention over a 26-day period. Furthermore, Fv-LDP-D3-AE, a pertinent antibody-drug conjugate prepared by integrating the enediyne chromophore of lidamycin into the Fv-LDP-D3 molecule, displayed highly potent cytotoxicity, inhibited migration and invasion, induced apoptosis and DNA damage, arrested cells at G2/M phase, and caused mitochondrial damage in esophageal cancer cells. More importantly, both of Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the growth of esophageal cancer xenografts in athymic mice at well tolerated doses. The present results indicate that Fv-LDP-D3, and Fv-LDP-D3-AE exert prominent antitumor efficacy associated with targeting EGFR, suggesting their potential as promising candidates for targeted therapy against esophageal cancer.


Assuntos
Neoplasias Esofágicas , Imunoconjugados , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Enedi-Inos/química , Enedi-Inos/farmacologia , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , IMP Desidrogenase/uso terapêutico , Imunoconjugados/metabolismo , Imunoconjugados/farmacologia , Camundongos , Camundongos Nus , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Phytomedicine ; 101: 154097, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35417848

RESUMO

BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is one of the most important drug-metabolizing enzymes in the human body, mainly existing in the liver, small intestine, and kidney. Panaxytriol is one of the key active components in red ginseng and Shenmai injection. Our previous study demonstrated that panaxytriol regulates CYP3A4 expression mainly by activating pregnancy X receptor (PXR). At a high concentration of panaxytriol (80 µM), the constitutive androstane receptor (CAR) is also involved in the upregulation of CYP3A4. PURPOSE: This study investigated how the cofactors heat shock protein 90 alpha (HSP90α) and retinoid X receptor alpha (RXRα) interact with PXR and CAR to participate in the regulation of CYP3A4 by panaxytriol from the perspective of the PXR and CAR interaction. METHODS: The mRNA and protein expressions of PXR, CAR, CYP3A4, RXRα, and HSP90α in HepG2 cells and Huh-7 cells were detected by quantitative PCR and western blot analysis, respectively. The binding levels of PXR and CAR to RXRα and HSP90α were determined by co-immunoprecipitation analysis. The nuclear translocation of PXR and RXRα into HepG2 cells and human (hCAR)-silenced HepG2 cells were measured by immunofluorescence. RESULTS: In HepG2 cells and Huh-7 cells, panaxytriol (10-80 µM) upregulated CYP3A4 expression in a concentration-dependent manner by decreasing PXR binding to HSP90α and increasing PXR binding to RXRα. When hCAR was silenced, panaxytriol further enhanced CYP3A4 expression by strengthening PXR binding to RXRα, but it had no significant effect on the binding level of PXR and HSP90α. Additionally, at the high concentration of 80 µM panaxytriol, CAR binding to HSP90α was weakened while binding to RXRα was enhanced. CONCLUSION: Panaxytriol can upregulate CYP3A4 expression by promoting PXR dissociation from HSP90α and enhancing PXR binding to RXRα in HepG2 cells and Huh-7 cells. At high concentrations of panaxytriol, CAR also participates in the induction of CYP3A4 through a similar mechanism. However, in general, CAR antagonizes PXR binding to RXRα, thereby attenuating the upregulation of CYP3A4 by panaxytriol.


Assuntos
Citocromo P-450 CYP3A , Receptores de Esteroides , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Enedi-Inos , Álcoois Graxos , Hepatócitos , Humanos , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/genética
3.
Org Biomol Chem ; 20(18): 3823-3834, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35470844

RESUMO

A concise and practical strategy towards a novel class of 14-membered macrocycles containing an enediyne (Z-3-ene-1,5-diyne) structural unit is described. A highly modular assembly of various precursors via sequential Ugi/Sonogashira reactions allowed the preparation of hybrid enediyne-peptide macrocycles in most cases as single diastereoisomers. Selected macrocyclic compounds showed moderate antiproliferative activity, and can be considered as templates suitable for further diversification in terms of ring size, shape, and stereochemistry.


Assuntos
Compostos Macrocíclicos , Enedi-Inos/química , Compostos Macrocíclicos/química , Peptídeos
4.
Int J Hyperthermia ; 39(1): 405-413, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35236209

RESUMO

BACKGROUND: Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of 'metalloenediynes' on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO4-PyED, an Fe co-factor complex of (Z)-N,N'-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells. METHODS: Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4-PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4-PyED at 37 or 42.5 °C. RESULTS: FeSO4-PyED is a DNA-binding compound. Enhancement of FeSO4-PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO4-PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. CONCLUSION: By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue.


Assuntos
Antineoplásicos , Hipertermia Induzida , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclização , Enedi-Inos/química , Enedi-Inos/farmacologia , Enedi-Inos/uso terapêutico , Temperatura Alta , Humanos , Camundongos
5.
Mol Pharm ; 19(4): 1078-1090, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35290067

RESUMO

Enediyne natural products, including neocarzinostatin and calicheamicin γ1, are used in the form of a copolymer or antibody-drug conjugate to treat hepatomas and leukemia. Tiancimycin (TNM) A is a novel anthraquinone-fused enediyne that can rapidly and completely kill tumor cells. Herein, we encapsulated TNM A in liposomes (Lip-TNM A) and cyclic arginine-glycine-aspartate (cRGD)-functionalized liposomes (cRGD-Lip-TNM A) and demonstrated its antitumor activity using mouse xenografts. Because TNM A causes rapid DNA damage, cell cycle arrest, and apoptosis, these nanoparticles exhibited potent cytotoxicity against multiple tumor cells for 8 h. In B16-F10 and KPL-4 xenografts, both nanoparticles showed superior potency over doxorubicin and trastuzumab. However, cRGD-Lip-TNM A reduced the tumor weight more significantly than Lip-TNM A in B16-F10 xenografts, in which the αvß3-integrin receptors are significantly overexpressed in this melanoma. Lip-TNM A was slightly more active than cRGD-Lip-TNM A against KPL-4 xenografts, which probably reflected the difference of their in vivo fate in this mouse model. In a highly metastatic 4T1 tumor model, cRGD-Lip-TNM A reduced tumor metastasis induced by losartan, a tumor microenvironment-remodeling agent. These findings suggest that targeted delivery of enediynes with unique modes of action may enable more effective translation of anticancer nanomedicines.


Assuntos
Neoplasias da Mama , Melanoma , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Enedi-Inos , Feminino , Humanos , Lipossomos , Melanoma/tratamento farmacológico , Camundongos , Microambiente Tumoral
6.
Chem Biodivers ; 19(1): e202100608, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34786852

RESUMO

A new globoscinic acid derivative, aspertubin A (1) along with four known compounds, were obtained from the co-culture of Aspergillus tubingensis S1120 with red ginseng. The chemical structures of compounds were characterized by using spectroscopic methods, the calculated and experimental electronic circular dichroism. Panaxytriol (2) from red ginseng, and asperic acid (4) showed significant antifeedant effect with the antifeedant rates of 75 % and 80 % at the concentrations of 50 µg/cm2 . Monomeric carviolin (3) and asperazine (5) displayed weak attractant activity on silkworm. All compounds were assayed for antifungal activities against phytopathogens A. tubingensis, Nigrospora oryzae and Phoma herbarum and the results indicated that autotoxic aspertubin A (1) and panaxytriol (2) possessed selective inhibition against A. tubingensis with MIC values at 8 µg/mL. The co-culture extract showed higher antifeedant and antifungal activities against P. herbarum than those of monoculture of A. tubingensis in ordinary medium. So the medicinal plant and endophyte showed synergistic effect on the plant disease resistance by active compounds from the coculture of A. tubingensis S1120 and red ginseng.


Assuntos
Antifúngicos/química , Aspergillus/química , Repelentes de Insetos/química , Panax/química , Animais , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Aspergillus/metabolismo , Bombyx/efeitos dos fármacos , Bombyx/crescimento & desenvolvimento , Enedi-Inos/química , Enedi-Inos/isolamento & purificação , Enedi-Inos/farmacologia , Álcoois Graxos/química , Álcoois Graxos/isolamento & purificação , Álcoois Graxos/farmacologia , Repelentes de Insetos/isolamento & purificação , Repelentes de Insetos/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Panax/crescimento & desenvolvimento , Panax/metabolismo , Phoma/efeitos dos fármacos , Plantas Medicinais/química , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo
7.
Nat Prod Rep ; 39(3): 703-728, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-34672308

RESUMO

Covering: up to the end of July, 2021Anthraquinone-fused enediynes (AFEs) are a subfamily of enediyne natural products. Dynemicin A (DYN A), the first member of the AFE family, was discovered more than thirty years ago. Subsequently, extensive studies have been reported on the mode of action and the interactions of AFEs with DNA using DYN A as a model. However, progress in the discovery, biosynthesis and clinical development of AFEs has been limited for a long time. In the past five years, four new AFEs have been discovered and significant progress has been made in the biosynthesis of AFEs, especially on the biogenesis of the anthraquinone moiety and their tailoring steps. Moreover, the streamlined total synthesis of AFEs and their analogues boosts the preparation of AFE-based linker-drugs, thus enabling the development of AFE-based antibody-drug conjugates (ADCs). This review summarizes the discovery, mechanism of action, biosynthesis, total synthesis and preclinical studies of AFEs.


Assuntos
Produtos Biológicos , Enedi-Inos , Antraquinonas/farmacologia , Produtos Biológicos/farmacologia , Enedi-Inos/farmacologia
8.
Acta Crystallogr F Struct Biol Commun ; 78(Pt 1): 1-7, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34981769

RESUMO

Dynemicin is an enediyne natural product from Micromonospora chersina ATCC53710. Access to the biosynthetic gene cluster of dynemicin has enabled the in vitro study of gene products within the cluster to decipher their roles in assembling this unique molecule. This paper reports the crystal structure of DynF, the gene product of one of the genes within the biosynthetic gene cluster of dynemicin. DynF is revealed to be a dimeric eight-stranded ß-barrel structure with palmitic acid bound within a cavity. The presence of palmitic acid suggests that DynF may be involved in binding the precursor polyene heptaene, which is central to the synthesis of the ten-membered ring of the enediyne core.


Assuntos
Enedi-Inos , Micromonospora , Cristalografia por Raios X , Enedi-Inos/química , Enedi-Inos/metabolismo , Micromonospora/genética , Micromonospora/metabolismo , Família Multigênica
9.
Anal Biochem ; 633: 114394, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34610334

RESUMO

Human apurinic/pyrimidine endonuclease 1 (APE1) played a critical role in the occurrence, progress and prognosis of tumors through overexpression and subcellular localization. Thus, it has become an important target for enhancing the sensitivity of tumor cells to radiotherapy and chemotherapy. Therefore, detecting and imaging its intracellular activity is of great significance for inhibitor discovery, cancer diagnosis and therapy. In this work, using DNA-based nanoprobe, we developed a new method for monitor intracellular APE1 activity. The detecting system was consisted by single fluorophore labeled hairpin probe and reduced graphene oxide (rGO). The in vitro result showed that a liner response of the detection method ranged from 0.02 U/mL to 2 U/mL with a limit of detection of 0.02 U/mL. Furthermore, this strategy possessing high specificity was successfully applied for APE1-related inhibitor screening using intracellular fluorescence imaging. Panaxytriol, an effective inhibitor of APE1 activity, was screened from traditional Chinese medicine (TCM) and its effect on APE1 activity was monitored in real time in A549 cells. In summary, this sensitive and specific APE1 detection technology is expected to provide an assistance for APE1-related inhibitor screening and diseases diagnosis.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/análise , DNA/química , Grafite/química , Nanopartículas/química , Células A549 , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Avaliação Pré-Clínica de Medicamentos , Enedi-Inos/farmacologia , Álcoois Graxos/farmacologia , Humanos , Imagem Óptica , Fatores de Tempo
10.
Acta Crystallogr F Struct Biol Commun ; 77(Pt 10): 328-333, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34605436

RESUMO

The 1.5 Šresolution crystal structure of DynU16, a protein identified in the dynemicin-biosynthetic gene cluster, is reported. The structure adopts a di-domain helix-grip fold with a uniquely positioned open cavity connecting the domains. The elongated dimensions of the cavity appear to be compatible with the geometry of a linear polyene, suggesting the involvement of DynU16 in the upstream steps of dynemicin biosynthesis.


Assuntos
Antraquinonas/metabolismo , Antibacterianos/biossíntese , Enedi-Inos/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Sequência de Aminoácidos , Cristalografia por Raios X , Modelos Moleculares , Família Multigênica , Conformação Proteica
11.
Biotechnol J ; 16(12): e2100250, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34473904

RESUMO

Yangpumicins (YPMs), for example, YPM A, F, and G, are newly discovered enediynes from Micromonospora yangpuensis DSM 45577, which could be exploited as promising payloads of antibody-drug conjugates. However, the low yield of YPMs in the wild-type strain (∼1 mg L-1 ) significantly hampers their further drug development. In this study, a combined ribosome engineering and fermentation optimization strategy has been used for yield improvement of YPMs. One gentamicin-resistant M. yangpuensis DSM 45577 strain (MY-G-1) showed higher YPMs production (7.4 ± 1.0 mg L-1 ), while it exhibits delayed sporulation and slender mycelium under scanning electron microscopy. Whole genome re-sequencing of MY-G-1 reveals several deletion and single nucleotide polymorphism mutations, which were confirmed by PCR and DNA sequencing. Further Box-Behnken experiment and regression analysis determined that the optimal medium concentrations of soluble starch, D-mannitol, and pharmamedia for YPMs production in shaking flasks (10.0 ± 0.8 mg L-1 ). Finally, the total titer of YPM A/F/G in MY-G-1 reached to 15.0 ± 2.5 mg L-1 in 3 L fermenters, which was about 11-fold higher than the original titer of 1.3 ± 0.3 mg L-1 in wild-type strain. Our study may be instrumental to develop YPMs into a clinical anticancer drug, and inspire the use of these multifaceted strategies for yield improvement in Micromonospora species. GRAPHICAL ABSTRACT LAY SUMMARY: ???


Assuntos
Micromonospora , Enedi-Inos , Fermentação , Micromonospora/genética , Ribossomos
12.
Biol Pharm Bull ; 44(7): 1024-1028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193685

RESUMO

Brain inflammation is a pathological characteristic of neurodegenerative diseases. In this condition, excessively activated microglia elevate proinflammatory mediator levels. We previously reported that panaxytriol inhibited lipopolysaccharide (LPS)-induced microglia activation in vitro. However, the effects of panaxytriol on microglia activation in vivo require confirmation. In the present study, we found that panaxytriol suppressed both microglia and astrocyte activation by injected LPS intracerebrally to mice with LPS-induced brain inflammation. Panaxytriol was more effective on microglia than astrocytes. Moreover, panaxytriol tended to reduce LPS-induced spontaneous motor activity dysfunction. These results suggested that panaxytriol could improve brain health by suppressing microglia activation in neurodegenerative diseases.


Assuntos
Encefalite/tratamento farmacológico , Enedi-Inos/uso terapêutico , Álcoois Graxos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Enedi-Inos/farmacologia , Álcoois Graxos/farmacologia , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
13.
ACS Chem Biol ; 16(7): 1172-1178, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34138533

RESUMO

Tiancimycin (TNM) A belongs to the anthraquinone-fused subfamily of enediyne natural products, and selected enediynes have been translated into clinical drugs. Previously, inactivation of tnmL in Streptomyces sp. CB03234 resulted in the accumulation of TNM B and TNM E, supporting the functional assignment of TnmL as a cytochrome P450 hydroxylase that catalyzes A-ring modification in TNM A biosynthesis. Herein, we report in vitro characterization of TnmL, revealing that (i) TnmL catalyzes two successive hydroxylations of TNM E, resulting in sequential production of TNM F and TNM C, (ii) TnmL shows a strict substrate preference, with the C-26 side chain playing a critical role in substrate binding, and (iii) TnmL demethylates the C-7 OCH3 group of TNM G, affording TNM F, thereby channeling the shunt product TNM G back into TNM A biosynthesis and representing a rare proofreading logic for natural product biosynthesis. These findings shed new insights into anthraquinone-fused enediyne biosynthesis.


Assuntos
Antraquinonas/metabolismo , Proteínas de Bactérias/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Enedi-Inos/metabolismo , Antraquinonas/química , Proteínas de Bactérias/química , Biocatálise , Sistema Enzimático do Citocromo P-450/química , Enedi-Inos/química , Hidroxilação , Streptomyces/enzimologia , Especificidade por Substrato
14.
J Mater Chem B ; 9(19): 4056-4064, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33949615

RESUMO

Combined photothermal therapy/chemotherapy by co-delivery of a photosensitizer (PS) and a chemotherapeutic drug has demonstrated great potential for cancer treatment. The intrinsic drawbacks of traditional drug delivery systems (DDSs), such as tedious synthetic procedures, side effects originated from the carrier materials, low loading efficiency, and uncontrolled drug release, however, have impaired their further advancement. On the other hand, enediyne antibiotics are highly cytotoxic toward cancer cells through the generation of lethal carbon radicals via thermal-induced cyclization, endowing them with great potential to achieve enhanced synergistic anticancer performance by incorporation with the photothermal effect of PS. To this end, a carrier-free and NIR/acid dual-responsive DDS was constructed for combined photothermal therapy/chemotherapy. The facile co-assembly of maleimide-based enediyne and PS IR820 was achieved in aqueous solution to give nanoparticles (EICN) with a hydrodynamic diameter of 90 nm and high stability. In vitro study confirmed the acid/NIR dual-responsive degradation and drug release, free radical generation and DNA-cleaving ability of EICN, which was accomplished by the corporation of enediyne and IR820 moieties. Further tests on HeLa cells verified the excellent synergistic anticancer performance of EICN including the improved cellular uptake, NIR-enhanced drug release, DNA damage and histone deacetylase inhibitor capacity. Overall, this carrier-free DDS with dual acid/NIR-responsivity would potentially provide new insights for the development of combined photothermal/chemotherapy.


Assuntos
Antineoplásicos/química , Enedi-Inos/química , Verde de Indocianina/análogos & derivados , Raios Infravermelhos , Nanopartículas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Clivagem do DNA/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Hipertermia Induzida , Verde de Indocianina/química , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo
15.
J Mater Chem B ; 9(22): 4502-4509, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34019610

RESUMO

Myers-Saito cycloaromatization (MSC) is the working mechanism of many natural enediyne antibiotics with high antitumor potency. However, the presence of the equilibrium between diradical and zwitterionic intermediates in MSC severely hinders further improvement in cytotoxicity toward tumor cells. To this end, a series of maleimide-based enediynes with cyclopropane moieties were synthesized for enhanced cytotoxicity toward tumor cells. By taking advantage of radical clock reactions, the diradical intermediates generated from MSC would rearrange to new diradicals with much longer separation and weaker interactions between two radical centers. The computational study suggested a low energy barrier (4.4 kcal mol-1) for the radical rearrangement through the cyclopropane ring-opening process. Thermolysis experiments confirmed that this radical rearrangement results in the formation of a new diradical intermediate, followed by abstracting hydrogen atoms from 1,4-cyclohexadiene. Interestingly, the DNA cleavage ability and cytotoxicity of enediynes were significantly enhanced after the introduction of cyclopropane moieties. In addition, these maleimide-based enediynes exhibited a similar cytotoxicity under hypoxic conditions to that under normoxic conditions, which is beneficial for treating solid tumors where hypoxic environments frequently lead to deteriorated efficiency of many antitumor drugs. Docking studies indicated that the diradical intermediate was located between the minor groove of DNA with a binding energy of -7.40 kcal mol-1, which is in favor of intracellular DNA damage, and thereby inducing cell death via an apoptosis pathway as suggested by immunofluorescence analysis.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Ciclopropanos/química , Enedi-Inos/química , Maleimidas/química , Oxigênio/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
16.
J Pharmacol Sci ; 145(3): 273-278, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33602508

RESUMO

Activated microglia induce brain inflammation and neuronal death. Panaxytriol, ((3R,9R,10R)-Heptadec-1-en-4,6-diyne-3,9,10-triol), is a component of Panax ginseng C. A. Meyer extracts and activates the Nrf2-ARE signaling pathway. However, little is known about its effects on activated microglia in the brain. In this study, we investigated the effect of panaxytriol on lipopolysaccharide (LPS)-induced activated microglia in BV-2 cells. Panaxytriol suppressed LPS-induced NO production and inhibited the increase in iNOS protein expression in BV-2 cells. Besides, panaxytriol inhibited the mRNA expression of proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6. The inhibitory effect of panaxytriol on microglia activation did not affect the Nrf2-ARE pathway and the MAPK pathway. However, panaxytriol suppressed LPS-induced NF-κB nuclear translocation. These results suggest that panaxytriol inhibits the LPS-induced activation of microglia via the inhibition of NF-κB signaling pathway.


Assuntos
Enedi-Inos/farmacologia , Álcoois Graxos/farmacologia , Microglia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/citologia , Linhagem Celular , Citocinas/metabolismo , Enedi-Inos/isolamento & purificação , Álcoois Graxos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Panax/química , Transdução de Sinais/genética
17.
Int J Legal Med ; 135(4): 1407-1411, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33506296

RESUMO

In recent years, recorded cases related to forensic botany and, in particular, of plant poisoning have become rare. We report on the medicolegal characteristics of an undetermined sudden death (USD) of a woman in which scene there were remnants of a vegetal peeling. After the autopsy, macroscopic findings reported multiorgan failure and requested the investigation of the cause of death. Postmortem blood was firstly investigated on cyanide toxicity presumptively coming from a yucca-like root; however, found cyanide levels were under normality. Because of the lack of morphological features of the encountered plant remains, a genetic nrDNA ITS2 sequence investigation was followed. The resulting DNA sequence could identify the evidence as the water dropwort (Oenanthe spp.) which contains oenanthotoxin, a potent toxin that may be fatal, similar to the more commonly found in hemlock Conium or cowbane Cicuta species. A liquid chromatography-tandem high resolution mass spectrometry (LC-QTOF MS) was later applied to analyse the vegetal extract and stomach content and successfully confirmed the toxin existence. Medicolegal and analytical findings at the forensic laboratory were described, where both biological and chemical techniques could successfully conjugate, as an interdisciplinary research, and explain premortem symptoms and postmortem findings. Present data can be helpful in future investigation on poisoning cases by conjugated polyacetylenes . The present work tries to emphasize the often undervalued plant evidence in legal medicine diagnosis in the context of an unexplained death.


Assuntos
Morte Súbita/etiologia , Enedi-Inos/envenenamento , Álcoois Graxos/envenenamento , Genética Forense , Toxicologia Forense , Oenanthe/envenenamento , Intoxicação por Plantas , Idoso de 80 Anos ou mais , Cromatografia Líquida , Código de Barras de DNA Taxonômico , Feminino , Humanos , Espectrometria de Massas em Tandem
18.
Biomed Res Int ; 2020: 3972390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376721

RESUMO

Hepatitis B is a global infectious disease, seriously endangering human health. Currently, there are mainly interferons and nucleoside analogues treatment of hepatitis B in the clinic, which have certain therapeutic effects on hepatitis B, but their side effects and drug resistance are increasingly prominent. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially natural products, which have novel, high efficiency, and low toxicity anti-HBV compounds with novel antiviral mechanisms. In this manuscript, the natural products (polysaccharides and 165 compounds) with the activity of antihepatitis B virus are discussed according to their chemical classes, including 14 phenylpropanoids, 8 flavonoids,12 xanthones, 13 anthroquinones, 47 terpenoids, 6 alkaloids, 15 enediynes, 11 aromatics, 18 phenylalanine dipeptides compounds, and 13 others. In addition, the anti-HBV mechanism and targets of natural product were also discussed. The aim of this review is to report new discoveries about anti-HBV natural products and to provide reference for researchers.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Alcaloides/química , Dipeptídeos/química , Enedi-Inos/química , Flavonoides/química , Humanos , Concentração Inibidora 50 , Lactonas/química , Fenilalanina/química , Polissacarídeos/química , Terpenos/química , Xantonas/química
19.
J Org Chem ; 85(15): 9808-9819, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32657121

RESUMO

Acyclic enediynes are generally inactive under physiological conditions to be used as antitumor agents like their natural enediyne counterparts. A new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) is uncovered to trigger the reactivity of acyclic enediynes. Through this mechanism, cascade 1,3-proton transfer processes are accelerated with the maleimide moiety at the ene position to enable the acyclic enediynes to undergo cycloaromatization and generate reactive radicals under physiological conditions. Computational studies suggest that the highest energy barrier for MARACA is 26.0 kcal/mol, much lower than that of Bergman cyclization pathway (39.6 kcal/mol). Experimental results show that maleimide-based enediynes exhibit low onset temperature, fast generation of radical species at 37 °C, and much faster reaction in aqueous solution than in nonpolar solvent, which is beneficial to achieve both high reactivity in physiological environment and high stability for storage and delivery in nonpolar media. The generated radical species are capable of causing high percentage of double-strand (ds) DNA cleavage, leading to significant cytotoxicity toward a panel of cancer cell lines with half inhibition concentration down to submicromolar level. Overall, the discovery of the MARACA mechanism provides a platform for designing novel acyclic enediynes with high potency for antitumor applications.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Ciclização , Enedi-Inos/farmacologia , Humanos , Maleimidas/farmacologia
20.
J Med Chem ; 63(15): 8432-8441, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32658465

RESUMO

The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.


Assuntos
Proteínas de Bactérias/metabolismo , Enedi-Inos/metabolismo , Imunoconjugados/metabolismo , Metiltransferases/metabolismo , Streptomyces/metabolismo , Proteínas de Bactérias/química , Biocatálise , Vias Biossintéticas , Cristalografia por Raios X , Enedi-Inos/química , Imunoconjugados/química , Metiltransferases/química , Modelos Moleculares , Conformação Proteica , Streptomyces/química , Especificidade por Substrato
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