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1.
J Med Chem ; 67(16): 14077-14094, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39115131

RESUMO

The radiohybrid (rh) concept to design targeted (and chemically identical) radiotracers for imaging or radionuclide therapy of tumors has gained momentum. For this strategy, a new bifunctional Silicon-based Fluoride Acceptor (SiFA) moiety (SiFA)SeFe was synthesized, endowed with improved hydrophilicity and high versatility of integration into rh-compounds. Preliminary radiolabeling and stability studies under different conditions were conducted using model bioconjugate peptides. Further, three somatostatin receptor 2 (sstR2)-targeted rh-compounds ((SiFA)SeFe-rhTATE1-3, TATE = (Tyr3)-octreotate) were developed. Compound (SiFA)SeFe-rhTATE3, enables labeling with 18F for PET imaging or chelation of 177Lu for therapy. The rh-compounds possess comparable receptor binding affinity and in vitro performance as good as the clinically proven gold standards. SstR2-specificity was further shown for (SiFA)SeFe-rhTATE2 using the chicken chorioallantoic membrane (CAM) model. The biodistribution of two compounds in mice showed high accumulation in tumors and excretion via the kidneys, demonstrating the clinical applicability of the (SiFA)SeFe moiety.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Receptores de Somatostatina , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Membrana Corioalantoide/metabolismo , Fluoretos/química , Radioisótopos de Flúor/química , Lutécio/química , Peptídeos/química , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptores de Somatostatina/metabolismo , Silício/química , Distribuição Tecidual , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Compostos de Ferro/química
2.
RSC Chem Biol ; 5(6): 481-482, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38846075

RESUMO

Angela Casini (Technical University of Munich, Germany), Hui Chao (Sun Yat-Sen University, China), Hongzhe Sun (University of Hong Kong, China), and Christopher J. Chang (University of California, Berkeley, United States) introduce the themed collection on 'Chemical biology of metals'.

3.
RSC Adv ; 14(12): 8145-8149, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38464693

RESUMO

A modular synthetic pathway for poly(diethyl vinylphosphonates) grafting-to gold nanoparticles is presented. Utilising an azide-dopamine derivative as nanoparticle coating agent, alkyne-azide click conditions were used to covalently tether the polymer to gold nanoparticles leading to stable and well distributed colloids for different applications.

4.
ACS Cent Sci ; 10(2): 242-250, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38435529

RESUMO

The discovery of the medicinal properties of platinum complexes has fueled the design and synthesis of new anticancer metallodrugs endowed with unique modes of action (MoA). Among the various families of experimental antiproliferative agents, organometallics have emerged as ideal platforms to control the compounds' reactivity and stability in a physiological environment. This is advantageous to efficiently deliver novel prodrug activation strategies, as well as to design metallodrugs acting only via noncovalent interactions with their pharmacological targets. Noteworthy, another justification for the advance of organometallic compounds for therapy stems from their ability to catalyze bioorthogonal reactions in cancer cells. When not yet ideal as drug leads, such compounds can be used as selective chemical tools that benefit from the advantages of catalytic amplification to either label the target of interest (e.g., proteins) or boost the output of biochemical signals. Examples of metallodrugs for the so-called "catalysis in cells" are considered in this Outlook together with other organometallic drug candidates. The selected case studies are discussed in the frame of more general challenges in the field of medicinal inorganic chemistry.

5.
J Physiol ; 602(13): 3111-3129, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38323926

RESUMO

Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.


Assuntos
Aquaporina 3 , Adesão Celular , Movimento Celular , Proliferação de Células , Melanoma , Aquaporina 3/metabolismo , Aquaporina 3/genética , Humanos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HEK293 , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia
6.
Chempluschem ; 89(4): e202300557, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37937471

RESUMO

A dinuclear gold(I) complex featuring a strongly donating bis-N-heterocyclic imine ligand was synthesised and characterised by different methods, including single crystal X-ray diffraction (SC-XRD) analysis. The compound has been tested for its antiproliferative effects in a panel of human cancer cell lines in vitro, showing highly selective anticancer effects, particularly against human A549 non-small cell lung cancer cells (NSCLC), with respect to non-tumorigenic cells (VERO). The accumulation of the compound in A549 and VERO cells was studied by high-resolution continuum source atomic absorption spectrometry (HRCS-AAS), revealing that the anticancer effects are not particularly related to the different amounts of gold taken up by the cells over 72 h. Enzyme inhibition studies to evaluate the activity of the seleno-enzyme thioredoxin reductase (TrxR) in cancer cell extracts show that the gold(I) compound is a potent inhibitor (IC50=0.567±0.208 µM), while the free ligand is ineffective. This result correlates with the observed compound's selectivity towards A549 cells overexpressing the enzyme.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Chlorocebus aethiops , Humanos , Ouro/química , Tiorredoxina Dissulfeto Redutase/metabolismo , Linhagem Celular Tumoral , Ligantes , Células Vero
7.
J Nucl Med ; 65(3): 481-484, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38124121

RESUMO

To elucidate potential benefits of the Auger-electron-emitting radionuclide 161Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip5-d-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (α-Me-Trp8-RM2), each labeled with both 177Lu and 161Tb. Methods: 161Tb/177Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice. Results: Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [161Tb]Tb-RM2, 2.46 ± 0.16; [161Tb]Tb-AMTG, 2.16 ± 0.09; [177Lu]Lu-RM2, 3.45 ± 0.18; [177Lu]Lu-AMTG, 3.04 ± 0.08), and 75%-84% of cell-associated activity was receptor-bound. In vivo, both AMTG analogs displayed distinctly higher stability (30 min after injection) and noticeably higher tumor retention than their RM2 counterparts. Conclusion: On the basis of preclinical results, [161Tb]Tb-/[177Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [161Tb]Tb-/[177Lu]Lu-RM2, particularly [161Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.


Assuntos
Elétrons , Receptores da Bombesina , Camundongos , Animais , Camundongos SCID , Distribuição Tecidual , Membrana Celular
8.
Chemistry ; 29(62): e202302375, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37555841

RESUMO

In the context of drug discovery, computational methods were able to accelerate the challenging process of designing and optimizing a new drug candidate. Amongst the possible atomistic simulation approaches, metadynamics (metaD) has proven very powerful. However, the choice of collective variables (CVs) is not trivial for complex systems. To automate the process of CVs identification, two different machine learning algorithms were applied in this study, namely DeepLDA and Autoencoder, to the metaD simulation of a well-researched drug/target complex, consisting in a pharmacologically relevant non-canonical DNA secondary structure (G-quadruplex) and a metallodrug acting as its stabilizer, as well as solvent molecules.


Assuntos
Aprendizado de Máquina , Simulação de Dinâmica Molecular , Solventes , Algoritmos , Termodinâmica
9.
Inorg Chem ; 62(50): 20710-20720, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-37556427

RESUMO

Self-assembled supramolecular coordination complexes (SCCs) hold promise for biomedical applications in cancer therapy, although their potential in the field of nuclear medicine is still substantially unexplored. Therefore, in this study an exo-functionalized cationic [Pd2L2]4+ metallacycle (L = 3,5-bis(3-ethynylpyridine)phenyl), targeted to the somatostatin-2 receptor (sst2R) and featuring the DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) in order to bind the ß-- and γ-emitter lutetium-177, was synthesized by self-assembly following ligand synthesis via standard solid-phase peptide synthesis (SPPS). This metallacycle was then characterized by reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionization mass spectrometry (ESI-MS), and 1H and 1H-DOSY NMR (DOSY = diffusion-ordered spectroscopy). A procedure for the radiolabeling of the metallacycle with 177Lu was also optimized. The resulting [nat/177Lu]Lu-DOTA-metallacycle, termed [nat/177Lu]Lu-Cy, was evaluated concerning its stability and in vitro properties. The compound was more lipophilic compared to the reference [177Lu]Lu-DOTA-TATE (logPOct/H2O = -0.85 ± 0.10 versus -3.67 ± 0.04, respectively). While [natLu]Lu-Cy revealed low stability in a DMEM/F12 GlutaMax medium, it demonstrated good stability in other aqueous media as well as in DMSO. A high sst2R binding affinity (expressed as IC50) was determined in CHOsst2 cells (Chinese hamster ovary cells that were stably transfected with human sst2R). Moreover, the metallacycle exhibited high human serum albumin binding, as assessed by high-performance affinity chromatography (HPAC), and moderate stability in human serum compared to [177Lu]Lu-DOTA-TATE (TATE = (Tyr3)-octreotate). In order to improve stability, a heteroleptic approach was used to develop a less sterically hindered cage-like SCC that is potentially endowed with host-guest chemistry capability, which has been preliminarily characterized by RP-HPLC and ESI-MS. Overall, our initial results encourage future studies on sst2R-directed SCCs and have led to new insights into the chemistry of ss2R-directed SCCs for radiopharmaceutical applications.


Assuntos
Medicina Nuclear , Compostos Radiofarmacêuticos , Animais , Cricetinae , Humanos , Células CHO , Cricetulus , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/química , Lutécio/química , Medicina Nuclear/métodos , Somatostatina
10.
J Inorg Biochem ; 247: 112346, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37536162

RESUMO

The limited chemical stability of gold(III)-based compounds in physiological environment has been a challenge in drug discovery, and organometallic chemistry might provide the solution to overcome this issue. In this work, four novel cationic organogold(III)-dithiocarbamate complexes of general structure [(C^N)AuIIIDTC]PF6 (C1a - C4a, DTC = dithiocarbamate, L1 - L4, C^N = 2-anilinopyridine) are presented, and compared to their coordination gold(III)-dithiocarbamate analogues [AuIIIDTCCl2] (C1b - C4b), as potential anti-cancer and anti-leishmanial drugs. Most of the complexes effectively inhibited cancer cell growth, notably C3a presented anti-proliferative effect in the nanomolar range against breast cancer (MCF-7 and MDA-MB-231 cells with moderate selectivity. Pro-apoptotic studies on treated MCF-7 cells showed a high population of cells in early apoptosis. Reactivity studies of C3a towards model thiols (N-acetyl-L-cysteine) refer to a possible mode of action involving bonding between the organogold(III)-core and the thiolate. In the scope of neglected diseases, gold complexes are emerging as promising therapeutic alternatives against leishmaniasis. In this regard, all gold(III)-dithiocarbamate complexes presented anti-leishmanial activity against at least one Leishmania species. Complexes C1a, C4a, C1b, C4b were active against all tested parasites with IC50 values varying between 0.12 and 42 µM, and, overall, organometallic compounds presented more intriguing inhibition profiles. For C4a selectivity over 500-fold for L. braziliensis; even higher than the reference anti-leishmanial drug amphotericin B. Overall, our findings revealed that the organogold(III) moiety significantly amplified the anti-cancer and anti-leishmanial effects with respect to the coordination analogues; thus, showing the great potential of organometallic chemistry in metallodrug-based chemotherapy for cancer and leishmaniasis.


Assuntos
Antineoplásicos , Leishmania , Compostos Organometálicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Organoáuricos/farmacologia , Compostos Organoáuricos/química , Ouro/química , Linhagem Celular Tumoral
11.
J Med Chem ; 66(14): 9823-9841, 2023 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-37410388

RESUMO

Two new 'hybrid' metallodrugs of Au(III) (AuTAML) and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Humanos , Feminino , Tamoxifeno/metabolismo , Complexos de Coordenação/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Mitocôndrias , Receptores de Estrogênio/metabolismo , Linhagem Celular Tumoral
12.
J Am Chem Soc ; 145(25): 13570-13580, 2023 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-37318835

RESUMO

Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination, and repair) and are dynamic structures that adopt either open or closed conformations, the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core, an ideal structure to interact with open DNA junction cavities. Combining experimental studies and MD simulations, we show that an Au pillarplex can bind DNA 4-way (Holliday) junctions in their open form, a binding mode not accessed by synthetic agents before. Pillarplexes can bind 3-way junctions too, but their large size leads them to open up and expand that junction, disrupting the base pairing, which manifests in an increased hydrodynamic size and lower junction thermal stability. At high loading, they rearrange both 4-way and 3-way junctions into Y-shaped forks to increase the available junction-like binding sites. Isostructural Ag pillarplexes show similar DNA junction binding behavior but lower solution stability. This pillarplex binding contrasts with (but complements) that of metallo-supramolecular cylinders, which prefer 3-way junctions and can rearrange 4-way junctions into 3-way junction structures. The pillarplexes' ability to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures. In human cells, the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher-order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction binders into organometallic chemistry.


Assuntos
DNA Cruciforme , Ácidos Nucleicos , Humanos , Conformação de Ácido Nucleico , DNA/química , Sítios de Ligação
13.
ACS Sens ; 8(7): 2525-2532, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37339775

RESUMO

Electrochemical detection methods are attractive for developing miniaturized, disposable, and portable sensors for molecular diagnostics. In this article, we present a cucurbit[7]uril-based chemosensor with an electrochemical signal readout for the micromolar detection of the muscle relaxant pancuronium bromide in buffer and human urine. This is possible through a competitive binding assay using a chemosensor ensemble consisting of cucurbit[7]uril as the host and an electrochemically active platinum(II) compound as the guest indicator. The electrochemical properties of the indicator are strongly modulated depending on the complexation state, a feature that is exploited to establish a functional chemosensor. Our design avoids cumbersome immobilization approaches on electrode surfaces, which are associated with practical and conceptual drawbacks. Moreover, it can be used with commercially available screen-printed electrodes that require minimal sample volume. The design principle presented here can be applied to other cucurbit[n]uril-based chemosensors, providing an alternative to fluorescence-based assays.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Imidazóis , Humanos , Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Eletrodos , Técnicas Eletroquímicas
14.
J Med Chem ; 66(6): 3995-4008, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36898000

RESUMO

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.


Assuntos
Platina , Neoplasias de Mama Triplo Negativas , Humanos , Platina/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Cafeína/uso terapêutico , Linhagem Celular Tumoral , Carboidratos/farmacologia , Nucleotídeos/farmacologia , Lipídeos/farmacologia , Proliferação de Células , Apoptose
15.
Angew Chem Int Ed Engl ; 62(22): e202218000, 2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-36847211

RESUMO

The discovery of the medicinal properties of gold complexes has fuelled the design and synthesis of new anticancer metallodrugs, which have received special attention due to their unique modes of action. Current research in the development of gold compounds with therapeutic properties is predominantly focused on the molecular design of drug leads with superior pharmacological activities, e.g., by introducing targeting features. Moreover, intensive research aims at improving the physicochemical properties of gold compounds, such as chemical stability and solubility in the physiological environment. In this regard, the encapsulation of gold compounds in nanocarriers or their chemical grafting onto targeted delivery vectors could lead to new nanomedicines that eventually reach clinical applications. Herein, we provide an overview of the state-of-the-art progress of gold anticancer compounds, andmore importantly we thoroughly revise the development of nanoparticle-based delivery systems for gold chemotherapeutics.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Ouro/química , Nanomedicina , Preparações Farmacêuticas , Sistemas de Liberação de Medicamentos , Compostos de Ouro/química , Neoplasias/tratamento farmacológico
16.
FEBS Lett ; 597(1): 191-202, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36345593

RESUMO

The field of Bioinorganic Supramolecular Chemistry is an emerging research area including metal-based supramolecules resulting from coordination-driven self-assembly (CDSA), whereby metal ions and organic ligands can be easily linked by metal-ligand bonds via Lewis' acid/base interactions. The focus of this 'In a Nutshell' review will be on the family of supramolecular coordination complexes, discrete entities formed by CDSA, which have recently captured widespread attention as a new class of versatile multifunctional materials with broad biological applications including molecular recognition, biosensing, therapy, imaging and drug delivery. Herein, we provide a summary of the state-of-the-art use of these systems in biomedicine, with some selected representative examples, as well as our visions of the challenges and possible directions in the field.


Assuntos
Complexos de Coordenação , Complexos de Coordenação/química , Metais , Sistemas de Liberação de Medicamentos/métodos
17.
Chemistry ; 29(3): e202202604, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36239701

RESUMO

To advance the design of self-assembled metallosupramolecular architectures as new generation theranostic agents, the synthesis of 18 F-labelled [Pd2 L4 ]4+ metallacages is reported. Different spectroscopic and bio-analytical methods support the formation of the host-guest cage-cisplatin complex. The biodistribution profiles of one of the cages, alone or encapsulating cisplatin have been studied by PET/CT imaging in healthy mice in vivo, in combination to ICP-MS ex vivo.


Assuntos
Antineoplásicos , Cisplatino , Camundongos , Animais , Cisplatino/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Distribuição Tecidual , Tomografia por Emissão de Pósitrons , Antineoplásicos/química
18.
Inorg Chem ; 61(50): 20405-20423, 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36484812

RESUMO

With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds' stabilization properties toward G4s of different topologies of physiological relevance. Initial structure-activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and free-energy landscape of the most active xanthine derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations evidenced that the Au(I) compound interacts noncovalently with the top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs free energy of binding were experimentally validated by FRET DNA melting assays. The compounds have also been tested for their antiproliferative properties in human cancer cells in vitro, showing generally moderate activity. This study provides further insights into the biological activity of Au(I) organometallics acting via noncovalent interactions and underlines their promise for tunable targeted applications by appropriate chemical modifications.


Assuntos
Quadruplex G , Humanos , Ligantes , DNA/química , Transferência Ressonante de Energia de Fluorescência , Xantinas
19.
Pharmaceuticals (Basel) ; 15(9)2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36145354

RESUMO

Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N4-bombesin derivatives this was addressed by substitutions at the Gln7-Trp8 site within the MJ9 peptide (H-Pip5-phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) either by homoserine (Hse7), ß-(3-benzothienyl) alanine (Bta8) or α-methyl tryptophan (α-Me-Trp8), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N4)-asp-MJ9, N4-asp-[Bta8]MJ9, N4-[Hse7]MJ9 and N4-[α-Me-Trp8]MJ9, and evaluated these compounds in vitro (GRPR affinity via IC50,inverse; internalization; lipophilicity via logD7.4) and in vivo (biodistribution and µSPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). 99mTc-labeling resulted in radiochemical yields (RCYs) > 95%. All 99mTc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [99mTc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta8-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln7-Trp8 site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging.

20.
Chemistry ; 28(56): e202201575, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-35801389

RESUMO

N-heterocyclic carbenes (NHCs) have become attractive ligands for functionalizing gold nanoparticle surfaces with applications ranging from catalysis to biomedicine. Despite their great potential, NHC stabilized gold colloids (NHC@AuNPs) are still scarcely explored and further efforts should be conducted to improve their design and functionalization. Here, the 'bottom-up' synthesis of two water-soluble gold nanoparticles (AuNP-1 and AuNP-2) stabilized by hydrophilic mono- and bidentate NHC ligands is reported together with their characterization by various spectroscopic and analytical methods. The NPs showed key differences likely to be due to the selected NHC ligand systems. Transmission electron microscopy (TEM) images showed small quasi-spherical and faceted NHC@AuNPs of similar particle size (ca. 2.3-2.6 nm) and narrow particle size distribution, but the colloids featured different ratios of Au(I)/Au(0) by X-ray photoelectron spectroscopy (XPS). Furthermore, the NHC@AuNPs were supported on titania and fully characterized. The new NPs were studied for their catalytic activity towards the reduction of nitrophenol substrates, the reduction of resazurin and for their photothermal efficiency. Initial results on their application in photothermal therapy (PTT) were obtained in human cancer cells in vitro. The aforementioned reactions represent important model reactions towards wastewater remediation, bioorthogonal transformations and cancer treatment.


Assuntos
Ouro , Nanopartículas Metálicas , Coloides , Ouro/química , Humanos , Ligantes , Nanopartículas Metálicas/química , Metano/análogos & derivados , Nitrofenóis , Águas Residuárias , Água
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