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1.
Inorg Chem ; 63(14): 6202-6216, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38385171

RESUMO

Ruthenium(II) complexes containing diimine ligands have contributed to the development of agents for photoactivated chemotherapy. Several approaches have been used to obtain photolabile Ru(II) complexes. The two most explored have been the use of monodentate ligands and the incorporation of steric effects between the bidentate ligands and the Ru(II). However, the introduction of electronic effects in the ligands has been less explored. Herein, we report a systematic experimental, theoretical, and photocytotoxicity study of a novel series of Ru(II) complexes Ru1-Ru5 of general formula [Ru(phen)2(N∧N')]2+, where N∧N' are different minimal strained ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole (BTAT) scaffold, being CH3 (Ru1), F (Ru2), CF3 (Ru3), NO2 (Ru4), and N(CH3)2 (Ru5) substituents in the R4 of the phenyl ring. The complexes are stable in solution in the dark, but upon irradiation in water with blue light (λex = 465 nm, 4 mW/cm2) photoejection of the ligand BTAT was observed by HPLC-MS spectrometry and UV-vis spectroscopy, with t1/2 ranging from 4.5 to 14.15 min depending of the electronic properties of the corresponding BTAT, being Ru4 the less photolabile (the one containing the more electron withdrawing substituent, NO2). The properties of the ground state singlet and excited state triplet of Ru1-Ru5 have been explored using density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. A mechanism for the photoejection of the BTAT ligand from the Ru complexes, in H2O, is proposed. Phototoxicity studies in A375 and HeLa human cancer cell lines showed that the new Ru BTAT complexes were strongly phototoxic. An enhancement of the emission intensity of HeLa cells treated with Ru5 was observed in response to increasing doses of light due to the photoejection of the BTAT ligand. These studies suggest that BTAT could serve as a photocleavable protecting group for the cytotoxic bis-aqua ruthenium warhead [Ru(phen)2(OH2)2]2+.


Assuntos
Neoplasias , Rutênio , Humanos , Quelantes , Rutênio/farmacologia , Rutênio/química , Ligantes , Células HeLa , Dióxido de Nitrogênio
2.
J Med Chem ; 67(1): 691-708, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38141031

RESUMO

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.


Assuntos
Antineoplásicos , Complexos de Coordenação , Dermatite Fototóxica , Neoplasias , Humanos , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Dermatite Fototóxica/tratamento farmacológico , Lisossomos , Benzotiazóis , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico
3.
Chem Sci ; 14(26): 7170-7184, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37416722

RESUMO

Photodynamic therapy (PDT) represents a promising approach for cancer treatment. However, the oxygen dependency of PDT to generate reactive oxygen species (ROS) hampers its therapeutic efficacy, especially against hypoxic solid tumors. In addition, some photosensitizers (PSs) have dark toxicity and are only activatable with short wavelengths such as blue or UV-light, which suffer from poor tissue penetration. Herein, we developed a novel hypoxia-active PS with operability in the near-infrared (NIR) region based on the conjugation of a cyclometalated Ru(ii) polypyridyl complex of the type [Ru(C^N)(N^N)2] to a NIR-emitting COUPY dye. The novel Ru(ii)-coumarin conjugate exhibits water-solubility, dark stability in biological media and high photostability along with advantageous luminescent properties that facilitate both bioimaging and phototherapy. Spectroscopic and photobiological studies revealed that this conjugate efficiently generates singlet oxygen and superoxide radical anions, thereby achieving high photoactivity toward cancer cells upon highly-penetrating 740 nm light irradiation even under hypoxic environments (2% O2). The induction of ROS-mediated cancer cell death upon low-energy wavelength irradiation along with the low dark toxicity exerted by this Ru(ii)-coumarin conjugate could circumvent tissue penetration issues while alleviating the hypoxia limitation of PDT. As such, this strategy could pave the way to the development of novel NIR- and hypoxia-active Ru(ii)-based theragnostic PSs fuelled by the conjugation of tunable, low molecular-weight COUPY fluorophores.

4.
Inorg Chem ; 62(16): 6474-6487, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37040203

RESUMO

We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)2]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-d:2',3'-f]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin. The promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Humanos , Relação Estrutura-Atividade , Osmio/farmacologia , Cálcio , Linhagem Celular Tumoral , Benzimidazóis/farmacologia , Homeostase , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia
5.
Dermatol Online J ; 25(12)2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32045170

RESUMO

Anti-programmed cell death (PD)-1 therapies in metastatic tumors have a high incidence of immune adverse events, including cutaneous manifestations such as vitiligo-like lesions. This side effect is associated with increased survival and it is a clinical marker of response to treatment. This case report is a graphic representation of the appearance of vitiligo-like lesions over in-transit metastases of malignant melanoma linked to a complete response to treatment with pembrolizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Vitiligo/induzido quimicamente , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Melanoma/secundário , Pele/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário
6.
Oncol Lett ; 12(4): 2936-2941, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27698882

RESUMO

The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin®) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment. Trabectedin is a novel treatment option for patients with ESFT. The present study reports the case of a Caucasian 69-year-old female patient who presented with a soft tissue mass on the chest wall that had developed 7 months earlier. A computed tomography scan revealed a 9×8×7-cm mass on the anterior chest wall above the pectoral muscle. Histopathological evaluations and molecular analysis indicated that it was consistent with a metastatic extraskeletal Ewing's sarcoma. The patient was treated with an alternating VAC/IE regimen; however, an inadequate response was observed. The patient received second-line treatment with a gemcitabine and dacarbazine combination regimen, but the disease progressed. Subsequently, treatment with trabectedin (1.5 mg/m2 as a 24-h continuous infusion every 3 weeks) was initiated. Trabectedin treatment resulted in long-lasting (18 months) progression-free survival. It is vital that novel drugs continue to being developed for patients with ESFT following progression subsequent to standard chemotherapy. The current report presents a case of a patient with metastatic, pre-treated Ewing's sarcoma achieving disease stabilization with trabectedin. Based on these results and the observed tolerability profile, trabectedin represents an alternative treatment for patients with ESFT. Further studies are required in order to determine the efficacy of trabectedin as monotherapy or in combination with other drugs. It is also important to identify which tumor subtypes, specific translocations and patient profiles will benefit the most from treatment with trabectedin.

7.
Oncol Lett ; 7(4): 1276-1278, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24944707

RESUMO

Anal cancer is a rare tumor that accounts for 2% of all colorectal neoplasms. The brain is a rarely affected organ. The aim of the present study was to the review the only four cases of anal cancer brain metastases previously published in the literature. In addition, the current study presents the case of a 69-year-old male diagnosed with basaloid undifferentiated carcinoma of the anal canal (stage IV with liver, lung and bone metastasis). Despite the patient's good response to chemotherapy and the achievement of a partial response that was maintained for 14 months, brain metastases developed. Although radiotherapy was administered, the patient succumbed to the condition 12 weeks after the diagnosis of brain metastasis.

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