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1.
Proc Natl Acad Sci U S A ; 117(13): 7021-7029, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32179677

RESUMO

Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.


Assuntos
Antineoplásicos/administração & dosagem , Metaloporfirinas/administração & dosagem , Oxaliplatina/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HCT116 , Humanos , Metaloporfirinas/farmacocinética , Camundongos Nus , Oxaliplatina/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Chem Soc Rev ; 51(14): 6177-6209, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35792133

RESUMO

In recent years, lanthanide (Ln) porphyrinoids have received increasing attention as theranostics. Broadly speaking, the term 'theranostics' refers to agents designed to allow both disease diagnosis and therapeutic intervention. This Review summarises the history and the 'state-of-the-art' development of Ln porphyrinoids as theranostic agents. The emphasis is on the progress made within the past decade. Applications of Ln porphyrinoids in near-infrared (NIR, 650-1700 nm) fluorescence imaging (FL), magnetic resonance imaging (MRI), radiotherapy, and chemotherapy will be discussed. The use of Ln porphyrinoids as photo-activated agents ('phototheranostics') will also be highlighted in the context of three promising strategies for regulation of porphyrinic triplet energy dissipation pathways, namely: regioisomeric effects, metal regulation, and the use of expanded porphyrinoids. The goal of this Review is to showcase some of the ongoing efforts being made to optimise Ln porphyrinoids as theranostics and as phototheranostics, in order to provide a platform for understanding likely future developments in the area, including those associated with structure-based innovations, functional improvements, and emerging biological activation strategies.


Assuntos
Elementos da Série dos Lantanídeos , Imageamento por Ressonância Magnética/métodos , Medicina de Precisão , Nanomedicina Teranóstica/métodos
3.
Chem Soc Rev ; 51(4): 1212-1233, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35099487

RESUMO

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances.


Assuntos
Antineoplásicos , COVID-19 , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Morte Celular Imunogênica , Imunoterapia , Neoplasias/terapia , Pandemias , SARS-CoV-2
4.
J Am Chem Soc ; 142(49): 20536-20541, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33237764

RESUMO

Immunogenic cell death (ICD) is a way of reengaging the tumor-specific immune system. ICD can be induced by treatment with chemotherapeutics. However, only a limited number of drugs and other treatment modalities have been shown to elicit the biomarker responses characteristic of ICD and to provide an anticancer benefit in vivo. Here, we report a rationally designed redox-active Au(I) bis-N-heterocyclic carbene that induces ICD both in vitro and in vivo. This work benefits from a synthetic pathway that allows for the facile preparation of asymmetric redox-active Au(I) bis-N-heterocyclic carbenes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/química , Ouro/química , Morte Celular Imunogênica/efeitos dos fármacos , Metano/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Metano/química , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo
5.
J Am Chem Soc ; 142(38): 16156-16160, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32914968

RESUMO

The NIR absorptivity of the metallotexaphyrin derivatives MMn, MGd, and MLu for photoacoustic (PA)-based imaging is explored in this study. All three complexes demonstrated excellent photostabilities; however, MMn provided the greatest PA signal intensities in both doubly distilled water and RAW 264.7 cells. In vivo experiments using a prostate tumor mouse model were performed. MMn displayed no adverse toxicity to major organs as inferred from hematoxylin and eosin (H&E) staining and cell blood count testing. MMn also allowed for PA-based imaging of tumors with excellent in vivo stability to provide 3D tumor diagnostic information. Based on the present findings and previous magnetic resonance imaging (MRI) studies, we believe MMn may have a role to play either as a stand-alone PA contrast agent or as a single molecule dual modal (PA and MR) imaging agent for tumor diagnosis.


Assuntos
Meios de Contraste/química , Manganês/química , Técnicas Fotoacústicas , Porfirinas/química , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Humanos , Raios Infravermelhos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Células RAW 264.7
6.
Chem Soc Rev ; 48(3): 771-813, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30575832

RESUMO

Hypoxia is a state of low oxygen tension found in numerous solid tumours. It is typically associated with abnormal vasculature, which results in a reduced supply of oxygen and nutrients, as well as impaired delivery of drugs. The hypoxic nature of tumours often leads to the development of localized heterogeneous environments characterized by variable oxygen concentrations, relatively low pH, and increased levels of reactive oxygen species (ROS). The hypoxic heterogeneity promotes tumour invasiveness, metastasis, angiogenesis, and an increase in multidrug-resistant proteins. These factors decrease the therapeutic efficacy of anticancer drugs and can provide a barrier to advancing drug leads beyond the early stages of preclinical development. This review highlights various hypoxia-targeted and activated design strategies for the formulation of drugs or prodrugs and their mechanism of action for tumour diagnosis and treatment.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Hipóxia Celular , Desenho de Fármacos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/uso terapêutico , Microambiente Tumoral
7.
J Am Chem Soc ; 141(39): 15611-15618, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31509395

RESUMO

Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN-38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Irinotecano/química , Irinotecano/farmacologia , Camundongos , Camundongos Nus , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Angew Chem Int Ed Engl ; 55(41): 12626-31, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27377046

RESUMO

Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present "activation by reduction" approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt(IV) prodrugs.


Assuntos
Antineoplásicos/química , Metaloporfirinas/química , Platina/química , Pró-Fármacos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas Eletroquímicas , Humanos , Oxirredução , Platina/farmacologia , Pró-Fármacos/farmacologia
9.
Chemistry ; 20(29): 8942-7, 2014 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-24961491

RESUMO

In an effort to increase the stability and control the platinum reactivity of platinum-texaphyrin conjugates, two Pt(IV) conjugates were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti-proliferative effects using wild-type and platinum-resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first-generation Pt(II) chimera, one of the new conjugates provided increased stability in aqueous environments. Using a combination of (1) H NMR spectroscopy and FAAS (flameless atomic-absorption spectrometry), it was found that the Pt(IV) center within this conjugate undergoes photoinduced reduction to Pt(II) upon exposure to glass-filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions in which the Pt(IV) complex is reduced to the corresponding Pt(II) species, these new conjugates demonstrated potent anti-proliferative activity in both test ovarian cancer cell lines.


Assuntos
Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/tratamento farmacológico , Porfirinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA/metabolismo , Desenho de Fármacos , Feminino , Humanos , Luz , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Oxirredução , Porfirinas/farmacologia
10.
Inorg Chem ; 52(21): 12184-92, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-23557113

RESUMO

Texaphyrins are pentaaza expanded porphyrins with the ability to form stable complexes with a variety of metal cations, particularly those of the lanthanide series. In biological milieus, texaphyrins act as redox mediators and mediate the production of reactive oxygen species (ROS). In this review, newer studies involving texaphyrin complexes targeting several different applications in anticancer therapy are described. In particular, the preparation of bismuth and lead texaphyrin complexes as potential α-core emitters for radiotherapy is detailed, as are gadolinium texaphyrin functionalized magnetic nanoparticles with features that make them of interest as dual-mode magnetic resonance imaging contrast agents and as constructs with anticancer activity mediated through ROS-induced sensitization and concurrent hyperthermia. Also discussed are gadolinium texaphyrin complexes as possible carrier systems for the targeted delivery of platinum payloads.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Bismuto/química , Chumbo/química , Nanopartículas de Magnetita/química , Porfirinas/química , Animais , Descoberta de Drogas , Humanos , Imageamento por Ressonância Magnética/métodos , Compostos de Platina/química , Compostos de Platina/farmacologia
11.
Curr Opin Chem Biol ; 73: 102277, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36867977

RESUMO

The immune system presents a complex array of processes designed to maintain homeostasis in malignant cellular growth. Malignancy is the result of a breakdown in immune surveillance by cancer cells evading immune recognition. Significant efforts have been made in modulating immune checkpoint signaling cascades to bypass the resulting immune evasion and establish an anticancer effect. More recently, it was discovered that a form of regulated cell death can involve the stimulation of immune response as its downstream effect and subsequently re-establish immune surveillance. This mechanism, known as immunogenic cell death (ICD), is being exploited as a target to prevent tumor relapse and prevent cancer metastasis. It is now appreciated that metal-based compounds play a key role in ICD activation due to their unique biochemical properties and interactions within cancer cells. With fewer than 1% of known anticancer agents documented as ICD inducers, recent efforts have been made to identify novel entities capable of stimulating a more potent anticancer immune response. While the recent reviews by us or others focus primarily on either discussing the chemical library of ICD inducers or intricate detailing of biological pathways associated with ICD, this review aims to bridge these two topics as a concise summary. Furthermore, early clinical evidence and future directions of ICD are briefly summarized.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Humanos , Complexos de Coordenação/farmacologia , Morte Celular Imunogênica , Morte Celular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/metabolismo
12.
Proc Natl Acad Sci U S A ; 106(38): 16068-73, 2009 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-19805260

RESUMO

This work describes the rational design, synthesis, and study of a ligand that selectively complexes CUG repeats in RNA (and CTG repeats in DNA) with high nanomolar affinity. This sequence is considered a causative agent of myotonic dystrophy type 1 (DM1) because of its ability to sequester muscleblind-like (MBNL) proteins. Ligand 1 was synthesized in two steps from commercially available compounds, and its binding to CTG and CUG repeats in oligonucleotides studied. Isothermal titration calorimetry studies of 1 with various sequences showed a preference toward the T-T mismatch (K(d) of 390 +/- 80 nM) with a 13-, 169-, and 85-fold reduction in affinity toward single C-C, A-A, and G-G mismatches, respectively. Binding and Job analysis of 1 to multiple CTG step sequences revealed high affinity binding to every other T-T mismatch with negative cooperativity for proximal T-T mismatches. The affinity of 1 for a (CUG)(4) step provided a K(d) of 430 nM with a binding stoichiometry of 1:1. The preference for the U-U in RNA was maintained with a 6-, >143-, and >143-fold reduction in affinity toward single C-C, A-A, and G-G mismatches, respectively. Ligand 1 destabilized the complexes formed between MBNL1N and (CUG)(4) and (CUG)(12) with IC(50) values of 52 +/- 20 microM and 46 +/- 7 microM, respectively, and K(i) values of 6 +/- 2 microM and 7 +/- 1 microM, respectively. These values were only minimally altered by the addition of competitor tRNA. Ligand 1 does not destabilize the unrelated RNA-protein complexes the U1A-SL2 RNA complex and the Sex lethal-tra RNA complex. Thus, ligand 1 selectively destabilizes the MBNL1N-poly(CUG) complex.


Assuntos
Proteínas de Ligação a RNA/química , RNA/química , Repetições de Trinucleotídeos , Acridinas/química , Acridinas/metabolismo , Sequência de Bases , Dicroísmo Circular , DNA/química , DNA/genética , DNA/metabolismo , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Conformação de Ácido Nucleico , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Ligação Proteica , RNA/genética , RNA/metabolismo , RNA de Transferência/química , RNA de Transferência/genética , RNA de Transferência/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Temperatura , Triazinas/química , Triazinas/metabolismo
13.
Dalton Trans ; 51(4): 1533-1541, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34989720

RESUMO

Unambiguous assignment of redox sites on ferrocene coupled N-heterocyclic carbene gold(I) complexes [(Fc-NHC)2Au(I)]+ is critical to gain a greater mechanistic understanding of their activity in a cellular environment. Such information can be garnered with isolation and detailed characterization of the oxidized version of [(Fc-NHC)2Au(I)]+. Herein we disclose a study that unambiguously illustrates redox events pertaining to [(Fc-NHC)2Au(I)]+ that stem exclusively from ferrocene sites. This work also describes novel synthetic methodologies for isolating ferrocenium coupled N-heterocyclic carbene gold(I) complexes.

14.
Bioact Mater ; 14: 76-85, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35310350

RESUMO

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, DOXjade, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading DOXjade onto ultrathin 2D Ti3C2 MXene nanosheets produces a construct, Ti 3 C 2 -PVP@DOXjade, that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, Ti 3 C 2 -PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.

15.
Bioorg Med Chem Lett ; 21(6): 1701-5, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21345675

RESUMO

In our effort to investigate further texaphyrin conjugation as a means of increasing delivery and accumulation of known anticancer platinum agents in cancer cells, we have continued our studies on the mode of action of a texaphyrin-platinum conjugate, particularly in cisplatin-resistant tumor cells that are characterized by several mechanisms of resistance, including reduced drug accumulation. Our results provide support for the proposal that intracellular platinum and Pt-DNA adduct levels were significantly increased using our conjugate relative to corresponding Pt controls. Moreover, no differences were found in cellular accumulation and Pt-DNA adduct formation between Pt sensitive and Pt resistant ovarian cells. As a result, resistance to the conjugate was lower than cisplatin in resistant cells. Based on these results we conclude that texaphyrin conjugation provides a promising strategy for overcoming biochemical pharmacologic mechanisms of resistance.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Porfirinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/patologia
16.
Chem Sci ; 12(21): 7547-7553, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-34163845

RESUMO

Recent decades have witnessed the emergence of Au(i) bis-N-heterocyclic carbenes (NHCs) as potential anticancer agents. However, these systems exhibit little interaction with serum proteins (e.g., human serum albumin), which presumably impacts their pharmacokinetic profile and tumor exposure. Anticancer drugs bound to human serum albumin (HSA) often benefit from significant advantages, including longer circulatory half-lives, tumor targeted delivery, and easier administration relative to the drug alone. In this work, we present Au(i) bis-NHCs complexes, 7 and 9, capable of binding to HSA. Complex 7 contains a reactive maleimide moiety for covalent protein conjugation, whereas its congener 9 contains a naphthalimide fluorophore for non-covalent binding. A similar drug motif was used in both cases. Complexes 7 and 9 were prepared from a carboxylic acid functionalized Au(i) bis-NHC (complex 2) using a newly developed post-synthetic amide functionalization protocol that allows coupling to both aliphatic and aromatic amines. Analytical, and in vitro techniques were used to confirm protein binding, as well as cellular uptake and antiproliferative activity in A549 human lung cancer cells. The present findings highlight a hitherto unexplored approach to modifying Au(i) bis-NHC drug candidates for protein ligation and serve to showcase the relative benefits of covalent and non-covalent HSA binding.

17.
Chem Sci ; 12(29): 9916-9921, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34377389

RESUMO

Photoacoustic imaging (PAI) relies on the use of contrast agents with high molar absorptivity in the NIR-I/NIR-II region. Expanded porphyrins, synthetic analogues of natural tetrapyrrolic pigments (e.g. heme and chlorophyll), constitute as potentially attractive platforms due to their NIR-II absorptivity and their ability to respond to stimuli. Here, we evaluate two expanded porphyrins, naphthorosarin (1) and octaphyrin (4), as stimuli responsive PA contrast agents for functional PAI. Both undergo proton-coupled electron transfer to produce species that absorb well in the NIR-II region. Octaphyrin (4) was successfully encapsulated into 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG2000) nanoparticles to afford OctaNPs. In combination with PAI, OctaNPs allowed changes in the acidic environment of the stomach to be visualized and cancerous versus healthy tissues to be discriminated.

18.
J Am Chem Soc ; 132(40): 14058-60, 2010 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-20853896

RESUMO

A pyrrolyl-based triazolophane, incorporating CH and NH donor groups, acts as a receptor for the pyrophosphate anion in chloroform solution. It shows selectivity for this trianion, followed by HSO(4)(-) > H(2)PO(4)(-) > Cl(-) > Br(-) (all as the corresponding tetrabutylammonium salts), with NH-anion interactions being more important than CH-anion interactions. In the solid state, the receptor binds the pyrophosphate anion in a clip-like slot via NH and CH hydrogen bonds.


Assuntos
Difosfatos/química , Pirróis/química , Triazóis/química , Ânions , Ligação de Hidrogênio
19.
Chem ; 6(7): 1634-1651, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33426365

RESUMO

Drawing inspiration from nature today remains a time-honored means of discovering the therapies of tomorrow. Porphyrins, the so-called "pigments of life" have played a key role in this effort due to their diverse and unique properties. They have seen use in a number of medically relevant applications, including the development of so-called drug conjugates wherein functionalization with other entities is used to improve efficacy while minimizing dose limiting side effects. In this Perspective, we highlight opportunities associated with newer, completely synthetic analogs of porphyrins, commonly referred to as porphyrinoids, as the basis for preparing drug conjugates. Many of the resulting systems show improved medicinal or site-localizing properties. As befits a Perspective of this type, our efforts to develop cancer-targeting, platinum-containing conjugates based on texaphyrins (a class of so-called "expanded porphyrins") will receive particular emphasis; however, the promise inherent in this readily generalizable approach will also be illustrated briefly using two other common porphyrin analogs, namely the corroles (a "contracted porphyrin") and porphycene (an "isomeric porphyrin").

20.
Chem ; 6(6): 1408-1419, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32864504

RESUMO

Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugating ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX), is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial relocalization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially-mediated oxidative damage.

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