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1.
Chem Commun (Camb) ; 57(70): 8806-8809, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34382631

RESUMO

The use of a triphenylarsonium vector for tumour cell-targeting leads to a dramatic increase in Gd3+ uptake in human glioblastoma multiforme cells by up to an order of magnitude over the isosteric triarylphosphonium analogue, with significant implications for 'theranostic' applications involving delivery of this important lanthanoid metal ion to tumour cells.


Assuntos
Antineoplásicos/química , Arsenicais/química , Quelantes/química , Gadolínio/química , Antineoplásicos/metabolismo , Arsenicais/metabolismo , Linhagem Celular Tumoral , Quelantes/metabolismo , Quelantes/toxicidade , Gadolínio/metabolismo , Humanos , Medicina de Precisão/métodos
2.
Chem Soc Rev ; 50(7): 4231-4244, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33599224

RESUMO

According to the World Health Organization (WHO), there were 18.1 million new cancer cases and 9.6 million cancer deaths reported worldwide in 2018. These numbers are expected to rise over the next decade, and the development of new and effective cancer treatments and diagnostic tools is urgently required, particularly for aggressive and intractable malignant cancers such as those of the brain. An exciting field of cancer research involves combining therapeutic and diagnostic tools into a single 'theranostic' platform. The role of theranostics in the personalized management of oncology patients is increasing, as is the demand for new types of theranostic agents. Some of the most promising cancer theranostics exploit the lanthanoid metal gadolinium, an element possessing favourable therapeutic and imaging properties.


Assuntos
Antineoplásicos/uso terapêutico , Gadolínio/uso terapêutico , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica , Antineoplásicos/química , Gadolínio/química , Humanos , Neoplasias/diagnóstico , Medicina de Precisão
3.
Sci Rep ; 11(1): 598, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436690

RESUMO

The synthesis of a new series of Gd(III)-arylphosphonium complexes is described and the solution stability of selected compounds is reported. Their lipophilicity and uptake in human glial (SVG p12) and human glioblastoma multiforme (T98G) cell lines are presented. The in vitro cytotoxicity of all complexes was determined to be low at therapeutically-relevant concentrations. Selected Gd(III) complexes are potential candidates for further investigation as theranostic agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Gadolínio/química , Glioblastoma/tratamento farmacológico , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Antineoplásicos/farmacocinética , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Compostos Organofosforados/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas
4.
J Med Chem ; 63(20): 11585-11601, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32678591

RESUMO

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.


Assuntos
Antimaláricos/síntese química , Compostos de Boro/química , Compostos Bicíclicos com Pontes/síntese química , Desenho de Fármacos , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Células Hep G2 , Humanos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos
5.
Chembiochem ; 21(19): 2786-2791, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32367603

RESUMO

Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50 =40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50 =42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.


Assuntos
Compostos de Boro/farmacologia , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/química , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular
7.
J Nat Prod ; 82(7): 1768-1778, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31282672

RESUMO

Usnic acid is a secondary metabolite abundantly found in lichens, for which promising cytotoxic and antitumor potential has been shown. However, knowledge concerning activities of its derivatives is limited. Herein, a series of usnic acid derivatives were synthesized and their antiproliferative potency against cancer cells of different origin was assessed. Some of the synthesized compounds were more active than usnic acid. Compounds 2a and 2b inhibited survival of all tested cancer cell lines in a dose- and time-dependent manner. Their IC50 values after 48 h of treatment were ca. 3 µM for MCF-7 and PC-3 cells and 1 µM for HeLa cells, while 3a and 3b revealed antiproliferative activity only against HeLa cells. All active usnic acid derivatives induced G0/G1 arrest and a drop in the fraction of HeLa cells in the S and G2/M phases. Compounds 2a and 2b decreased the clonogenic potential of the cancer cells evaluated and induced cell cycle arrest at the G0/G1 phase and apoptosis in MCF-7 cells. Moreover, they induced massive cytoplasmic vacuolization, which was associated with elevated dynein-dependent endocytosis, a process that has not been reported for usnic acid and indicates a novel mechanism of action of its synthetic derivatives. This work also shows that naturally occurring usnic acids are promising lead compounds for the synthesis of derivatives with more favorable properties against cancer cells.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/química , Benzofuranos/química , Células HeLa , Humanos , Células MCF-7
8.
J Med Chem ; 62(3): 1078-1095, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30137982

RESUMO

Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Química Farmacêutica/métodos , Cicloparafinas/farmacologia , Animais , Hidrocarbonetos Aromáticos com Pontes/síntese química , Técnicas de Química Sintética/métodos , Cicloparafinas/síntese química , Células HEK293 , Humanos , Camundongos , Ratos
9.
Chem Asian J ; 13(21): 3321-3327, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30369074

RESUMO

Novel boron-rich, carboranyl-indole carboxamide ligands were prepared and found to effectively target the 18 kDa translocator protein (TSPO), an upregulated mitochondrial membrane-bound protein which has been observed in variety of tumor cell lines and its expression appears to be proportional to the degree of tumorigenicity, emphasizing a key role in cancer cell proliferation. Both boronated compounds displayed remarkably high affinities for the TSPO. In addition, the in vitro uptake of these compounds into T98G human glioma cells was found to be 25- to 100-fold greater than that of clinical boron neutron capture therapy (BNCT) agents.

10.
J Inorg Biochem ; 177: 313-321, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28732658

RESUMO

The synthesis of a series of bifunctional Gd(III) complexes 1-3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake.


Assuntos
Complexos de Coordenação/farmacologia , Gadolínio/química , Oniocompostos/farmacologia , Compostos Organofosforados/farmacologia , Linhagem Celular Tumoral/metabolismo , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/toxicidade , Humanos , Mitocôndrias/metabolismo , Estrutura Molecular , Oniocompostos/química , Oniocompostos/metabolismo , Oniocompostos/toxicidade , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Compostos Organofosforados/toxicidade
11.
Chem Asian J ; 12(14): 1704-1708, 2017 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-28640518

RESUMO

The use of fluorescent markers and probes greatly enhances biological investigations but relies on the provision of an array of fluorophores with diverse properties. Herein we report a novel carborane-containing coumarin, 5, which is sufficiently lipophilic to localise in cellular lipid droplets. In non-polar solvents which show comparable polarities to those of a lipid environment, compound 5 exhibits a fluorescence quantum yield two orders of magnitude greater than found in aqueous solvents, adding a further degree of selectivity to lipid droplet imaging. Compound 5 can stain lipid droplets in ex vivo adipocytes as well as in cultured cells, and can be utilised in flow cytometry as well as confocal microscopy.


Assuntos
Boranos/química , Cumarínicos/química , Corantes Fluorescentes/química , Lipídeos/química , Células 3T3-L1 , Animais , Linhagem Celular Tumoral , Fluorescência , Humanos , Macrófagos/química , Camundongos , Estrutura Molecular , Tamanho da Partícula , Células RAW 264.7
12.
J Labelled Comp Radiopharm ; 60(1): 4-11, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28078681

RESUMO

Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨm ). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50  > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined.


Assuntos
Radioisótopos de Gálio/química , Compostos Organofosforados/química , Compostos Radiofarmacêuticos/síntese química , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Soro/efeitos dos fármacos
13.
Org Biomol Chem ; 14(39): 9388-9405, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27714195

RESUMO

The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.


Assuntos
Diaminas/química , Diaminas/metabolismo , Receptores sigma/metabolismo , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Etilenodiaminas/química , Cobaias , Ligantes , Piperazina , Piperazinas/química , Ensaio Radioligante , Ratos , Receptores sigma/química , Relação Estrutura-Atividade
14.
Chem Commun (Camb) ; 52(6): 1290-2, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26627051

RESUMO

We report the first example of an ionic graphene salt containing boron. An anionic charge is introduced to the graphene surface by means of 7,8-nido-[C2B9H11](-) carborane clusters covalently and electronically bound to the graphene lattice, and this new material was isolated as its Cs(+) salt.

15.
J Med Chem ; 58(21): 8743-9, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26461041

RESUMO

We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores de GABA/metabolismo , Acetamidas/química , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Ligação Proteica , Pirimidinas/química
16.
Dalton Trans ; 44(21): 9766-81, 2015 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-25939355

RESUMO

Two C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes, 1-(BMes2)-2-R-1,2-C2B10H10 (1, R = H, 2, R = Ph), were synthesised by lithiation of 1,2-dicarba-closo-dodecaborane and 1-phenyl-1,2-dicarba-closo-dodecaborane, respectively, with n-butyllithium and subsequent reaction with fluorodimesitylborane. These novel compounds were structurally characterised by X-ray crystallography. Compounds 1 and 2 are hydrolysed on prolonged exposure to air to give mesitylene and boronic acids 1-(B(OH)2)-2-R-1,2-C2B10H10 (3, R = H, 4, R = Ph respectively). Addition of fluoride anions to 1 and 2 resulted in boryl-carborane bond cleavage to give dimesitylborinic acid HOBMes2. UV absorption bands at 318-333 nm were observed for 1 and 2 corresponding to local π-π*-transitions within the dimesitylboryl groups while visible emissions at 541-664 nm with Stokes shifts of 11 920-16 170 cm(-1) were attributed to intramolecular charge transfer transitions between the mesityl and cluster groups. Compound was shown by cyclic voltammetry to form a stable dianion on reduction. NMR spectra for the dianion [](2-) were recorded from solutions generated by reductions of 2 with alkali metals and compared with NMR spectra from reductions of 1,2-diphenyl-ortho-carborane 5. On the basis of observed and computed (11)B NMR shifts, these nido-dianions contain bowl-shaped cluster geometries. The carborane is viewed as the electron-acceptor and the mesityl group is the electron-donor in C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes.

17.
Drug Discov Today ; 20(5): 609-17, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25478733

RESUMO

Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.


Assuntos
Antineoplásicos/uso terapêutico , Dioxigenases/antagonistas & inibidores , Descoberta de Drogas , Fatores Imunológicos/uso terapêutico , Cinurenina/metabolismo , Triptofano/metabolismo , Animais , Antineoplásicos/química , Domínio Catalítico , Dioxigenases/química , Dioxigenases/metabolismo , Humanos , Fatores Imunológicos/química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Modelos Moleculares , Terapia de Alvo Molecular , Conformação Proteica , Relação Estrutura-Atividade , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/metabolismo
18.
Chemistry ; 20(50): 16602-12, 2014 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-25323923

RESUMO

A structure-activity relationship study of a library of novel bifunctional Gd(III) complexes covalently linked to arylphosphonium cations is reported. Such complexes have been designed for potential application in binary cancer therapies such as neutron capture therapy and photon activation therapy. A positive correlation was found between lipophilicity and cytotoxicity of the complexes. Mitochondria uptake was determined by means of inductively coupled plasma mass spectrometry (ICP-MS), and Gd uptake was determined by means of quantification using synchrotron X-ray fluorescence (XRF) imaging. A negative correlation between lipophilicity and tumour selectivity of the Gd(III) complexes was demonstrated. This study highlights the delicate balance required to minimise in vitro cytotoxicity and optimise in vitro tumour selectivity and mitochondrial localisation for this new class of mitochondrially-targeted binary therapy agents. We also report the highest in vitro tumour selectivity for any Gd agent reported to date, with a T/N (tumour/normal cell) ratio of up to 23.5±6.6.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Gadolínio/química , Gadolínio/farmacologia , Mitocôndrias/metabolismo , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Gadolínio/farmacocinética , Humanos , Espectrometria de Massas , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organofosforados/farmacocinética , Espectrometria por Raios X
19.
Chem Commun (Camb) ; 50(77): 11332-4, 2014 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-25116510

RESUMO

The conjugated aromatic system of graphene was used to trap the reactive, boron-rich 1,2-carborane cluster. Functionalization of the graphene surface was confirmed by solid-state MAS (11)B NMR spectroscopy and quantified by X-ray photoelectron spectroscopy. This work represents the first confirmed example of direct functionalization of a graphene lattice with carboranes.

20.
Dalton Trans ; 43(28): 10719-24, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-24752804

RESUMO

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low µM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 µM.


Assuntos
Compostos de Boro/síntese química , Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Naftoquinonas/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Difração de Raios X
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