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1.
Chem Commun (Camb) ; 56(7): 1042-1045, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868189

RESUMO

A novel enzyme-responsive supramolecular polysaccharide assembly composed of disulfide linked adamantane-naphthalimide fluorescent camptothecin prodrug (AdaCPT) and ß-CD modified hyaluronic acid (HACD) was constructed, possessing low cellular cytotoxicity and exhibiting targeted cellular imaging and controlled drug release at specific sites while providing a concurrent means for the real-time tracking of drug delivery.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/farmacologia , Pró-Fármacos/farmacologia , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Adamantano/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Camptotecina/síntese química , Camptotecina/toxicidade , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HCT116 , Humanos , Ácido Hialurônico/química , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Células NIH 3T3 , Naftalimidas/síntese química , Naftalimidas/farmacologia , Naftalimidas/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , beta-Ciclodextrinas/química
2.
Analyst ; 144(22): 6681-6688, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31599280

RESUMO

The anticancer mechanism of NO is difficult to study owing to its short lifetime and high reactivity. Thus, a theranostic anticancer NO donor assembled with NO on-demand release abilities, accurate lysosome location capabilities and signal feedback behavior was developed. Profiting from the theranostic properties, the specific mechanism was comprehensively studied. Spectral and cell imaging studies revealed that the as prepared NO donors could release NO in solution or within cancer cells. Fluorescence co-dyeing experiments demonstrated that Mo-Nap-NO entered lysosomes specifically and disrupted them after being triggered by light. Upon irradiation with 460 nm visible light, both the donors demonstrated considerable in vitro anticancer effects. A further mechanistic study showed that after entering the lysosome and being triggered by 460 nm irradiation, NO ruptured the lysosome, resulting in the release of cathepsin D into the cytosol, which activated the caspase3 mediated apoptosis pathway.


Assuntos
Antineoplásicos/farmacologia , Corantes Fluorescentes/farmacologia , Lisossomos/metabolismo , Naftalimidas/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitrosaminas/farmacologia , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/efeitos da radiação , Humanos , Luz , Naftalimidas/efeitos da radiação , Doadores de Óxido Nítrico/efeitos da radiação , Nitrosaminas/efeitos da radiação , Nanomedicina Teranóstica/métodos
3.
Inorg Chem ; 58(19): 13150-13160, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31539237

RESUMO

Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum(II) complex cis-[Pt(NP)(NH3)2Cl]NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of PtNP was fully characterized by single-crystal X-ray crystallography, NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and in vivo anticancer activities with low systemic toxicity. The interaction of PtNP with CT-DNA demonstrated that PtNP could effectively bind to DNA through both covalent and noncovalent double binding modes. In addition to causing significant damage to nDNA and remarkable inhibition to DNA damage repair, PtNP also distributed in mitochondria, inducing mtDNA damage and affecting the downstream transcriptional level of mitochondrion-encoded genes. In addition, PtNP disturbed the physiological processes of mitochondria by reducing the mitochondrial membrane potential and promoting the generation of reactive oxygen species. Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. As a dual-DNA-damage agent, PtNP is able to improve the anticancer activity by damaging both nuclear and mitochondrial DNA, thus providing a new anticancer mechanism of action for the naphthalimide monofunctional platinum(II) complexes.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Substâncias Intercalantes/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos ICR , Modelos Moleculares , Naftalimidas/química , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Compostos Organoplatínicos/química , Piridinas/química , Piridinas/farmacologia
4.
Eur J Med Chem ; 181: 111599, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408807

RESUMO

In this work, five naphthalimide-modified half-sandwich iridium and ruthenium complexes ([(η5-Cpx)Ir(NˆN)Cl]PF6, [(η6-p-cym)Ru(NˆN)Cl]PF6) have been presented. The anticancer activities of the complexes against various cancer cell lines were investigated, among them, complexes 2 and 4 showed better anticancer activity than cisplatin, and their anticancer activity is better than complex 5 without fluorophore. In addition, a series of biological tests of complex 2 were performed using flow cytometry, the results indicated that the complex could induce cell death in a variety of ways. By changing of the ligands, the complexes exhibited different photophysical properties, and the mechanism of action of the complexes entering the cell and inducing apoptosis are different. Moreover, complex 2 successfully targeted mitochondria, while complex 4 targeted lysosomes, causing mitochondrial damage and lysosomal damage to induce apoptosis. Excitingly, complex 2 has good antimetastatic ability to cancer cells. Furthermore, complexes 2 and 4 did not have a significant effect on the NADH binding reaction, but they had a moderate binding ability to BSA.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Naftalimidas/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Irídio/química , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Naftalimidas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Rutênio/química
5.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146414

RESUMO

AMP-activated protein kinase (AMPK) has been implicated in contractility changes in bladders with partial bladder outlet obstruction (PBOO), but the role of AMPK in the contractile response of normal bladder remains unclear. We investigated the phosphorylation of AMPKα and expression of the involved upstream AMPK kinases (AMPKKs) in a model of bladders with PBOO and sought to determine whether the pharmacological inhibition of these two factors affected detrusor contractility in normal bladders, using female Sprague-Dawley rats. Cystometry and Western blot analysis were performed in rats that were subjected to PBOO induction or a sham operation. Cystometry was performed in normal rats that received selective inhibitors of AMPKα and Ca2+/calmodulin-dependent protein kinase kinase (CaMKKß) (compound C and STO-609, respectively) at doses determined in the experiments. In the PBOO bladders, bladder weight and micturition pressure (MP) were higher and AMPKα phosphorylation (T172) and CaMKKß expression was significantly reduced. Compound C and STO-609 increased MP. The increased contractile response in bladders with PBOO-induced hypertrophy was related to decreased CaMKKß/AMPK signaling activity, and the pharmacological inhibition of this pathway in normal bladders increased detrusor contractility, implying a role of CaMKKß/AMPK signaling in the bladder in the regulation of detrusor contractility.


Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Contração Muscular , Proteínas Quinases/metabolismo , Obstrução do Colo da Bexiga Urinária/metabolismo , Bexiga Urinária/metabolismo , Micção , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Feminino , Naftalimidas/farmacologia , Naftalimidas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico
6.
Eur J Med Chem ; 177: 401-413, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158753

RESUMO

Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.


Assuntos
DNA/metabolismo , Quadruplex G/efeitos dos fármacos , Naftalimidas/farmacologia , Linhagem Celular Tumoral , DNA/genética , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Naftalimidas/química , Naftalimidas/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
7.
Org Biomol Chem ; 17(21): 5349-5366, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31099353

RESUMO

A series of novel naphthalimide-benzimidazoles was designed and synthesized for the first time and studied for their effect on antiproliferative activity. Some of these compounds possessed good antitumor activity towards the tested cancer cell lines. Noticeably, (diethylamino)ethyl 15 and (dimethylamino)ethyl 23 derivatives displayed superior antiproliferative activity towards human cancer cell lines with MG_MID GI50 values of 1.43 and 1.83 µM, respectively. Preliminary investigation revealed that compounds 15 and 23 might bind with ct-DNA through the intercalation mode which is responsible for potent bioactivity. Moreover, transportation behaviour indicated that these molecules could efficiently bind to and be carried by bovine albumin, and the hydrogen bonding and hydrophobic interactions played important roles in interaction with serum albumin.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Naftalimidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Naftalimidas/química , Albumina Sérica/química , Albumina Sérica/efeitos dos fármacos , Relação Estrutura-Atividade
8.
J Agric Food Chem ; 67(22): 6387-6396, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31090403

RESUMO

Insect chitinolytic ß- N-acetylhexosaminidase OfHex1, from the agricultural pest Ostrinia furnacalis (Guenée), is considered as a potential target for green pesticide design. In this study, rational molecular design and optimization led to the synthesis of compounds 15r ( Ki = 5.3 µM) and 15y ( Ki = 2.7 µM) that had superior activity against OfHex1 than previously reported lead compounds. Both compounds 15r and 15y had high selectivity toward OfHex1 over human ß- N-acetylhexosaminidase B (HsHexB) and human O-GlcNAcase (hOGA). In addition, to investigate the basis for the potency of glycosylated naphthalimides against OfHex1, molecular docking and molecular dynamics simulations were performed to study possible binding modes. Furthermore, the in vivo biological activity of target compounds with efficient OfHex1 inhibitory potency was assayed against Myzus persicae, Plutella xylostella, and O. furnacalis. This present work indicates that glycosylated naphthalimides can be further developed as potential pest control and management agents targeting OfHex1.


Assuntos
Inibidores Enzimáticos/síntese química , Proteínas de Insetos/antagonistas & inibidores , Inseticidas/síntese química , Mariposas/enzimologia , Naftalimidas/síntese química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Animais , Avaliação de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosilação , Humanos , Proteínas de Insetos/química , Inseticidas/química , Inseticidas/farmacologia , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mariposas/efeitos dos fármacos , Naftalimidas/química , Naftalimidas/farmacologia , beta-N-Acetil-Hexosaminidases/química
9.
Int J Mol Sci ; 20(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027360

RESUMO

Neonatal hypoxia-ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium/calmodulin-dependent protein kinase kinase ß (CaMKK ß) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK ß in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK ß knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK ß KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood-brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK ß inhibition. In conclusion, inhibition of CaMKK ß exacerbated neonatal hypoxia-ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic-ischemic brain injury.


Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Hipóxia-Isquemia Encefálica/enzimologia , Hipóxia-Isquemia Encefálica/patologia , Animais , Animais Recém-Nascidos , Benzimidazóis/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Western Blotting , Morte Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naftalimidas/farmacologia
10.
Drug Dev Ind Pharm ; 45(8): 1306-1312, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30995142

RESUMO

Purpose: Studies have determined that UNBS5162, recognized as a new naphthalimide, holds inhibitory effects in prostate and breast tumors; however, its functional implication on gastric carcinoma is currently undetermined. Based on this, this study designed to assess the functional role of it on human gastric carcinoma and underlying mechanism of action. Methods: Cell counting kit-8 (CCK-8) assay, transwell assay, and flow cytometry were used to assess capabilities of SGC-7901 cell proliferation, invasion/migration, and apoptosis, respectively. Moreover, western blot was performed to determine the relative expression of protein related to autophagy and protein kinase B (AKT)/extracellular regulated protein kinases (ERK) signaling pathway. Results: We found SGC-7901 cells proliferation, invasion, and migration were significantly inhibited after treatment of UNBS5162. Moreover, the expression levels of anti-apoptotic protein Bcl-2 decreased while the expression of pro-apoptotic protein active caspase 3 and Bax increased concurrently after UNBS5162 stimulation. Further, upregulated LC3 II/I and Beclin-1 and downregulated P62 were induced by UNBS5162 addition. Mechanically, the ratios of phosphorylated-(p-)AKT/AKT, p-mammalian target of rapamycin (mTOR)/mTOR, and p-ERK/ERK were hampered by UNBS5162 application. Conclusion: UNBS5162 could restrain gastric carcinoma cell proliferation, invasion, and migration, which maybe induced by enhancement of apoptosis, autophagy manipulated through AKT/ERK signaling pathway.


Assuntos
Carcinoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Naftalimidas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Ureia/análogos & derivados , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Invasividade Neoplásica/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos , Ureia/farmacologia
11.
PLoS One ; 14(1): e0211420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695053

RESUMO

Capsaicin is a natural compound present in chili and red peppers and the responsible of their spicy flavor. It has recently provoked interest because of its antitumoral effects in many cell types although its action mechanism is not clearly understood. As metabolic dysregulation is one of the hallmarks of cancer cells and the key metabolic sensor in the AMP-activated kinase (AMPK), in this study we explored the ability of capsaicin to modulate AMPK activity. We found that capsaicin activated AMPK in HepG2 cells by increasing AMPK phosphorylation and its downstream target ACC. Mechanistically, we determined that capsaicin activated AMPK through the calcium/calmodulin-dependent protein kinase kinase ß, CaMKKß as either the CaMKK inhibitor STO-609 or CaMKK knock down with siRNA abrogated the activation of AMPK. Moreover, capsaicin decreased cell viability, inhibited Akt/mTOR pathway and increased reactive oxygen species (ROS) in HepG2 cells. AMPK activation was involved in the underpinning mechanism of capsaicin-induced cell death.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Capsaicina/farmacologia , Capsicum/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fármacos do Sistema Sensorial/farmacologia , Benzimidazóis/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Sobrevivência Celular , Ativação Enzimática , Células Hep G2 , Humanos , Naftalimidas/farmacologia , Fosforilação , Transdução de Sinais
12.
Med Chem ; 15(5): 550-560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30207241

RESUMO

BACKGROUND: The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA. OBJECTIVE: To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity. METHODS: The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines. RESULTS: Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide. CONCLUSION: The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.


Assuntos
Antineoplásicos/farmacologia , Naftalimidas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalimidas/síntese química , Naftalimidas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
13.
Med Chem ; 15(5): 537-549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30501600

RESUMO

BACKGROUND: Scientists have extensively investigated curcumin, yielding many publications on treatments of cancer. Numerous derivatives of curcumin were synthesized, evaluated for their anti-oxidant and free-radical scavenging, SAR, ADME properties and tested in anticancer applications. OBJECTIVE: We decided to exploit curcumin as a bioactive core platform for carrying anticancer drugs, which likely possesses a carboxyl moiety for potential linkage to the carrier for drug delivery. METHODS: The goal of this work is to develop biolabile multifunctional curcumin platforms towards anticancer drug delivery, including determination of drug release profiling in hydrolytic media, in vitro cytotoxicity, antioxidant properties and blockage of relevant cell survival pathways. RESULTS: We report on a facile synthesis of the bioactive multifunctional curcumin-based platforms linked to a variety of anticancer drugs like amonafide and chlorambucil, and release of the drugs in a hydrolytic environment. The leading curcumin-based platform has presented antioxidant activity similar to curcumin, but with much more potent cytotoxicity in vitro in agreement with the augmented blockage of the NF-kB cell survival pathway. CONCLUSION: The approach presented here may prove beneficial for bioactive curcumin-based delivery applications where multiple drug delivery is required in a consecutive and controlled mode.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Portadores de Fármacos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular Tumoral , Clorambucila/síntese química , Clorambucila/química , Clorambucila/farmacologia , Curcumina/síntese química , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Humanos , Naftalimidas/síntese química , Naftalimidas/química , Naftalimidas/farmacologia , Fosforilação/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/química , Fator de Transcrição RelA/metabolismo
14.
Int J Mol Sci ; 19(12)2018 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-30544880

RESUMO

The p38 MAPK pathway is known to influence the anti-tumor effects of several chemotherapeutics, including that of organometallic drugs. Previous studies have demonstrated the important role of p38 both as a regulator and a sensor of cellular reactive oxygen species (ROS) levels. Investigating the anti-cancer properties of novel 1,8-naphthalimide derivatives containing Rh(I) and Ru(II) N-heterocyclic carbene (NHC) ligands, we observed a profound induction of ROS by the complexes, which is most likely generated from mitochondria (mtROS). Further analyses revealed a rapid and consistent activation of p38 signaling by the naphthalimide-NHC conjugates, with the Ru(II) analogue-termed MC6-showing the strongest effect. In view of this, genetic as well as pharmacological inhibition of p38α, attenuated the anti-proliferative and pro-apoptotic effects of MC6 in HCT116 colon cancer cells, highlighting the involvement of this signaling molecule in the compound's toxicity. Furthermore, the influence of MC6 on p38 signaling appeared to be dependent on ROS levels as treatment with general- and mitochondria-targeted anti-oxidants abrogated p38 activation in response to MC6 as well as the molecule's cytotoxic- and apoptogenic response in HCT116 cells. Altogether, our results provide new insight into the molecular mechanisms of naphthalimide-metal NHC analogues via the ROS-induced activation of p38 MAPK, which may have therapeutic interest for the treatment of various cancer types.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/patologia , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Naftalimidas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rutênio/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Compostos Heterocíclicos/química , Humanos , Ligantes , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metano/química , Metano/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Naftalimidas/química , Rutênio/química , Transdução de Sinais/efeitos dos fármacos
15.
Med Sci (Paris) ; 34 Focus issue F1: 99-104, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30403183

RESUMO

Colon cancer is a common cause of cancer-related death worldwide. However, the underlying mechanism of tumor progression of colon cancer remains far from being elucidated. In the present study, we report the role of UNBS5162 in colon cancer. UNBS5162 is a naphthalimide that can intercalate into DNA and suppress the expression level of CXCL chemokines. Here, we investigated its effect on cell proliferation, mobility and apoptosis in HCT116 cells, and explored the underlying mechanism. A CCK8 assay revealed that UNBS5162 can block the proliferation of colon cancer cells. Base on a Transwell assay, we showed that cell migration and invasion ability of HCT116 cells are inhibited by UNBS5162. In addition, Annexin V-FITC/PI assay and Western blot analysis were performed to detect whether UNBS5162 could induce cell apoptosis. The results indicated that UNBS5162 increases the number of apoptotic cells remarkably. Furthermore, Western blot analysis demonstrated that UNBS5162 down-regulates the expression level of Bcl2, and up-regulates that of Bax as well as the level of activated Caspase-3. Moreover, we examined the impact of UNBS5162 on PI3K/Akt signaling pathway. UNBS5162 substantially inhibited the phosphorylation of Akt and its downstream effector mTOR, and reduced the expression of p-70. Taken together, these results suggest that UNBS5162 should be considered as a potent therapeutic anticancer agent that targets the PI3K/AKT signaling pathway.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Naftalimidas/farmacologia , Ureia/análogos & derivados , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ureia/farmacologia
16.
Eur J Med Chem ; 159: 393-422, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30312931

RESUMO

In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer agents. The 1,8-naphthalimides binds to the DNA via intercalation, and exert their antitumor activities through Topoisomerase I/II inhibition, photoinduced DNA damage or related mechanism. Here, our discussion focused on works published over the last ten years (2007-2017) related to therapeutic applications, in the order of cancer treatment followed by other properties of 1,8-naphthalimides. In preparing for this review, we considered that several seminal reviews have appeared over the last fifteen years and focused on closely related subjects, however, none of them is exhaustive.


Assuntos
Antineoplásicos/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/química , Humanos , Substâncias Intercalantes/química , Naftalimidas/química , Neoplasias/patologia , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/química
17.
Mol Med Rep ; 18(3): 3382-3388, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066877

RESUMO

UNBS5162, a novel naphthalimide, is generated by UNBS3157 hydrolysis in physiological saline. In the present study, the effects of UNBS5162 on M14 human melanoma cells were evaluated by Cell Counting Kit­8 and transwell assays, as well as western blotting. The underlying mechanism of apoptosis induced by UNBS5162 was investigated. The results demonstrated that proliferation of UNBS5162­treated M14 melanoma cells was markedly inhibited in a time­dependent manner. The flow cytometry results indicated a markedly increased apoptosis rate in the experimental group compared with in the control group (23.8±0.4 vs. 7.62±0.5%). Microscopy analysis revealed that the invasive and migratory abilities of UNBS5162­treated M14 cells were markedly suppressed. Furthermore, UNBS5162 treatment led to decreased expression of the anti­apoptotic protein B­cell lymphoma 2, but increased expression of the pro­apoptotic proteins Bcl­2­associated X protein and caspase­3. In addition, the expression of several key proteins involved in the phosphatidylinositol­4,5­bisphosphate 3­kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway was altered in M14 cells treated with UNBS5162. Based on these results, it may be hypothesized that UNBS5162 suppresses the proliferation of M14 cells by inducing apoptosis via inhibition of key proteins in the PI3K/Akt/mTOR signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Melanoma/metabolismo , Naftalimidas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Melanoma/patologia , Ureia/farmacologia
18.
Eur J Pharm Sci ; 124: 127-136, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153524

RESUMO

Naphthalimide platinum(IV) antitumor complexes with potential dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The incorporation of DNA targeted naphthalimide group to the platinum(IV) system exerts much positive impacts on their antitumor efficacy. The mechanism research reveals that the title compounds could interact with dsDNA in platinum(IV) form via the naphthalimide group and cause DNA lesion. The further reduction would release platinum(II) complexes and naphthalimide acids which would induce remarkable secondary damage to DNA. Furthermore, the naphthalimide platinum(IV) compounds could combine with human serum albumin via electrostatic force, which are favourable for their storage and transport in blood. Moreover, the title compounds exhibit higher accumulation in tumor cells, and exert lower toxic and higher safe properties than oxaliplatin in vivo.


Assuntos
Antineoplásicos/farmacologia , Naftalimidas/farmacologia , Compostos Organoplatínicos/farmacologia , Linhagem Celular Tumoral , Dano ao DNA , Humanos
19.
Virol J ; 15(1): 120, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081955

RESUMO

BACKGROUND: The results of our previous study showed that impaired cellular energy metabolism contributes to duck enteritis virus-induced autophagy via the 5`-adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2/mammalian target of rapamycin pathway in duck embryo fibroblast (DEF) cells. However, it remains unknown whether any other underlying mechanisms of AMPK activation are involved in autophagy induction. METHODS: The activity of CaMKKß and AMPK in DEF cells infected with DEV were evaluated.The Effect of inhibitory activity of CaMKKß on DEV-induced autophagy was investigated. In addtion to, the cytosolic calcium level in DEF cells infected with DEV were evaluated.The Effect of inhibitory cytosolic calcium level on DEV-induced autophagy was investigated. RESULTS: In this study, duck enteritis virus (DEV) infection activated CaMKKß and its substrate molecule AMPK at 36, 48, and 60 h post-infection (hpi). STO-609, a CaMKKß inhibitor, or CaMKKß siRNA significantly inhibited the activation of DEV to AMPK, LC3I to LC3II transformation, and GFP-LC3 puncta distribution. In addition, inhibition of CaMKKß activity also significantly reduced progeny DEV titer and gB protein expression. Besides, cytosolic calcium (Ca2+) was higher in DEV-infected cells than mock controls at 36, 48, and 60 hpi, respectively. Treatment of DEV-infected cells with 1,2-Bis (2-aminophenoxy) ethane-N, N, N', N-tetraacetic acid (BAPTA-AM) significantly reduced intracellular Ca2+ ion concentrations, as well as CaMKKß and AMPK activities, and subsequent autophagy, in addition to viral protein synthesis and viral titer. CONCLUSIONS: These results showed that elevated [Ca2+]cyto-mediated activation of CaMKKß managed the activation of AMPK, which then positively regulated autophagy, thereby providing further insight into DEV-host interactions.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Mardivirus/fisiologia , Transdução de Sinais , Animais , Antígenos Virais/genética , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Benzimidazóis/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Células Cultivadas , Citosol/metabolismo , Patos , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Fibroblastos/patologia , Fibroblastos/virologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Naftalimidas/farmacologia , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas do Envelope Viral/genética , Proteínas Virais/genética
20.
Eur J Med Chem ; 156: 148-161, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006161

RESUMO

Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Corantes Fluorescentes/química , Substâncias Intercalantes/química , Naftalimidas/química , Ródio/química , Rutênio/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/farmacologia , Quadruplex G/efeitos dos fármacos , Humanos , Substâncias Intercalantes/farmacologia , Ligantes , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Ródio/farmacologia , Rutênio/farmacologia
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