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1.
Pharmaceutics ; 13(11)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34834395

RESUMO

The highly secure blood-brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades-their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.

2.
Bioorg Med Chem ; 28(23): 115774, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32992251

RESUMO

A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P3 analogues exhibited sub-micromolar EC50 values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series.


Assuntos
Sulfonas/química , Tripanossomicidas/síntese química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia , Tioureia/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos
3.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075008

RESUMO

Haemostatic disorders are both complex and costly in relation to both their treatment and subsequent management. As leading causes of mortality worldwide, there is an ever-increasing drive to improve the diagnosis and prevention of haemostatic disorders. The field of microfluidic and Lab on a Chip (LOC) technologies is rapidly advancing and the important role of miniaturised diagnostics is becoming more evident in the healthcare system, with particular importance in near patient testing (NPT) and point of care (POC) settings. Microfluidic technologies present innovative solutions to diagnostic and clinical challenges which have the knock-on effect of improving health care and quality of life. In this review, both advanced microfluidic devices (R&D) and commercially available devices for the diagnosis and monitoring of haemostasis-related disorders and antithrombotic therapies, respectively, are discussed. Innovative design specifications, fabrication techniques, and modes of detection in addition to the materials used in developing micro-channels are reviewed in the context of application to the field of haemostasis.


Assuntos
Técnicas Biossensoriais , Hemostasia , Transtornos Hemostáticos/diagnóstico , Microfluídica/métodos , Transtornos Hemostáticos/patologia , Humanos , Dispositivos Lab-On-A-Chip , Sistemas Automatizados de Assistência Junto ao Leito , Qualidade de Vida
4.
Bioorg Med Chem ; 28(5): 115261, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987694

RESUMO

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Antineoplásicos/química , Benzopiranos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular
5.
J Med Chem ; 61(2): 514-534, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28426931

RESUMO

Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERß expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERß. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERß in cancer cells.


Assuntos
Benzoxepinas/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Receptor alfa de Estrogênio/química , Receptor beta de Estrogênio/química , Humanos , Ligantes , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , Proteólise/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 31(sup3): 117-130, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27476825

RESUMO

The estrogen receptors (ERα and ERß) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel ß-lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERα and ERß receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50 = 186 nM) and ERα binding (IC50 = 4.3 nM) with 75-fold ERα/ß receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the ß-lactam scaffold) on the antiproliferative activity and ER-binding properties of the ß-lactam compounds is rationalized in a molecular modeling study.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , beta-Lactamas/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/síntese química , Receptor beta de Estrogênio/antagonistas & inibidores , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , beta-Lactamas/síntese química
7.
J Med Chem ; 57(22): 9370-82, 2014 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-25369367

RESUMO

Twelve novel ß-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERß, were determined. ß-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERß (IC50 values: 19 and 15 nM). ß-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and ß-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.


Assuntos
Antagonistas do Receptor de Estrogênio/química , Tubulina (Proteína)/química , beta-Lactamas/química , Apoptose , Divisão Celular , Química Farmacêutica/métodos , Simulação por Computador , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/química , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/química , Estrogênios/química , Fase G2 , Humanos , Concentração Inibidora 50 , L-Lactato Desidrogenase/química , Ligantes , Células MCF-7 , Modelos Moleculares , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/química , Software , Sais de Tetrazólio/química , Tiazóis/química
8.
J Med Chem ; 56(17): 6638-50, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-23952916

RESUMO

A series of vinyl sulfone-containing peptidomimetics were rationally designed, synthesized, and evaluated against Trypanosoma brucei brucei . These electrophilic compounds are likely to exert their antitrypanosomal activity via inhibition of trypanosomal cysteine proteases, TbCatB and rhodesain, through alkylation of a key cysteine residue within the protease active site. The series was designed to present complementary groups to naturally recognized peptide substrates while probing tolerance to a range of substitutions at the P1, P1', and P2 positions. The most potent compound, 29 (EC50 = 70 nM, T. b. brucei whole cell assay), displayed minimal toxicity (>785 times selectivity) when assayed for cytotoxicity against the human promyelocytic leukemia (HL-60) cell line. Cells treated with compound 29, as with K777 (2), exhibited an increase in both the number of multinucleated cells and cells with swollen flagellar pockets. Computational analysis revealed a strong correlation between the hypothetical binding mode in TbCatB/rhodesain and trypanocidal activity in vitro.


Assuntos
Peptidomiméticos , Sulfonas/química , Sulfonas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Animais , Desenho de Fármacos , Células HL-60 , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Análise Espectral , Trypanosoma brucei brucei/efeitos dos fármacos
9.
Nephrol Dial Transplant ; 27(3): 1035-41, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21810765

RESUMO

BACKGROUND: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). METHODS: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. RESULTS: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. CONCLUSIONS: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/genética , Homozigoto , Mutação/genética , Erros Inatos do Transporte Tubular Renal/genética , Ácido Úrico/sangue , Cálculos Urinários/genética , Adulto , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Linhagem , Erros Inatos do Transporte Tubular Renal/sangue , Cálculos Urinários/sangue , Xenopus laevis/genética , Xenopus laevis/metabolismo , Adulto Jovem
10.
Bioorg Med Chem ; 19(20): 6055-68, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21920765

RESUMO

Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the lead identification of novel inhibitors based on ß-lactam and imine templates. ß-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC(50) values of 5.6 µM, 14.5 µM, and 22.1 µM, respectively. The binding affinity displayed by these compounds positions them as lead compounds for the design of future inhibitors of heat shock protein 90 based on the ß-lactam and imine templates.


Assuntos
Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Iminas/antagonistas & inibidores , beta-Lactamas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/química
11.
Eur J Med Chem ; 46(9): 4595-607, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21840628

RESUMO

The structure-activity relationships of antiproliferative ß-lactams, focusing on modifications at the 4-position of the ß-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 µM. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells.


Assuntos
Azetidinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Modelos Moleculares , Linhagem Celular Tumoral , Cristalografia por Raios X , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Microscopia Confocal , Microscopia de Fluorescência , Espectrofotometria Infravermelho
12.
Bioorg Med Chem ; 19(3): 1328-48, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21227702

RESUMO

Structural derivatives of 4-MTA, an illegal amphetamine analogue have been previously shown to have anticancer effects in vitro. In this study we report the synthesis of a series of novel 1,3-bis(aryl)-2-nitro-1-propene derivatives related in structure to 4-MTA. A number of these compounds containing a classic nitrostyrene structure are shown to have antiproliferative activities in vitro in a range of malignant cell lines, particularly against Burkitt's lymphoma derived cell lines, whilst having no effect on 'normal' peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt's lymphoma derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Nitrocompostos/síntese química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Alcenos/química , Antineoplásicos/química , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Estrutura Molecular , Nitrocompostos/química , Nitrocompostos/farmacologia , Serotonina/metabolismo
13.
Eur J Med Chem ; 45(12): 5752-66, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20933304

RESUMO

The synthesis and study of the structure-activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (ß-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. 12d exerts antimitotic effects through an inhibition of tubulin polymerisation and subsequent G2/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel ß-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estilbenos/síntese química , Estilbenos/farmacologia , beta-Lactamas/química , Animais , Antineoplásicos/química , Bovinos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Estilbenos/química , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
14.
ACS Chem Biol ; 5(10): 967-79, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20677820

RESUMO

In eukaryotic cells, proteins and RNAs are transported between the nucleus and the cytoplasm by nuclear import and export receptors. Over the past decade, small molecules that inhibit the nuclear export receptor CRM1 have been identified, most notably leptomycin B. However, up to now no small molecule inhibitors of nuclear import have been described. Here we have used our automated confocal nanoscanning and bead picking method (CONA) for on-bead screening of a one-bead one-compound library to identify the first such import inhibitor, karyostatin 1A. Karyostatin 1A binds importin ß with high nanomolar affinity and specifically inhibits importin α/ß mediated nuclear import at low micromolar concentrations in vitro and in living cells, without perturbing transportin mediated nuclear import or CRM1 mediated nuclear export. Surface plasmon resonance binding experiments suggest that karyostatin 1A acts by disrupting the interaction between importin ß and the GTPase Ran. As a selective inhibitor of the importin α/ß import pathway, karyostatin 1A will provide a valuable tool for future studies of nucleocytoplasmic trafficking.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , beta Carioferinas/antagonistas & inibidores , beta Carioferinas/metabolismo , Células HeLa , Humanos , Ligação Proteica/efeitos dos fármacos , beta Carioferinas/química , Proteína ran de Ligação ao GTP/metabolismo
15.
J Enzyme Inhib Med Chem ; 25(2): 180-94, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20222762

RESUMO

We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure-activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.


Assuntos
Antineoplásicos Fitogênicos , Benzoxepinas , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Estilbenos/química , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Benzoxepinas/síntese química , Benzoxepinas/química , Benzoxepinas/farmacologia , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
Mol Inform ; 29(5): 421-30, 2010 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27463197

RESUMO

A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor α (ERα) antagonist dataset, and successfully deployed for the identification of novel antagonists of ERα from a screening collection of ca. 160 000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ERα binding chemotypes were identified and biologically validated - demonstrating the applicability of a tiered intervention for virtual screening.

17.
Eur J Med Chem ; 44(12): 4862-88, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19717215

RESUMO

The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well as cytotoxic activity. While there was no direct correlation between these two effects, a number of derivatives displayed anti-tumour effects in lymphoma, leukaemia and breast cancer cell lines, showing further potential to be developed as possible chemotherapeutic agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fenetilaminas/síntese química , Fenetilaminas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Enxofre , Anfetaminas/síntese química , Anfetaminas/química , Anfetaminas/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Fenetilaminas/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Relação Estrutura-Atividade , Enxofre/química
18.
J Med Chem ; 52(8): 2177-80, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19331414

RESUMO

We describe the discovery of a novel indazole-based scaffold that represents the "first-in-class" dual Hsp90/tubulin binding compound. Individual known ligands for both targets shared similar 3',4',5'-trimethoxyphenyl cores, and from this it was hypothesized that application of an integrated ligand and structure-based virtual screening (VS) workflow could yield a single scaffold with dual binding affinity. Following validation of the VS protocol, we successfully identified a novel dual inhibitor, sourced from a commercial screening collection of 160 000 compounds.


Assuntos
Antineoplásicos/química , Bases de Dados Factuais , Proteínas de Choque Térmico HSP90/metabolismo , Imidazóis/química , Indazóis/química , Relação Quantitativa Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Trifosfato de Adenosina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Biopolímeros , Linhagem Celular Tumoral , Colchicina/metabolismo , Receptor alfa de Estrogênio/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Ligantes , Modelos Moleculares , Análise de Componente Principal , Ligação Proteica , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
19.
Bioorg Med Chem ; 16(21): 9554-73, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18835176

RESUMO

The estrogen receptors ERalpha and ERbeta are recognized as important pharmaceutical targets for a variety of diseases including osteoporosis and breast cancer. A series of novel benzoxepin-derived compounds are described as potent selective modulators of the human estrogen receptor modulators (SERMs). We report the antiproliferative effects of these compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the triarylethylene arrangement as exemplified by tamoxifen, conformationally restrained through the incorporation of the benzoxepin ring system. The compounds demonstrate potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity together with low nanomolar binding affinity for the estrogen receptor. The compounds also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzoxepin molecular scaffold is examined through a detailed docking and 2D-QSAR computational investigation. The best QSAR model developed for ERalphabeta selectivity yielded R(2) of 0.84 with an RMSE for the training set of 0.30. The predictive quality of the model was Q(2) of 0.72 and RMSE of 0.18 for the test set. One particular compound bearing a 4-fluoro substituent, exhibits 15-fold selectivity for ERbeta and both our docking and QSAR studies converge on the correlation between enhanced lipophilicity and enhanced ERbeta binding for this benzoxepin ring scaffold.


Assuntos
Benzoxepinas/síntese química , Moduladores de Receptor Estrogênico/síntese química , Benzoxepinas/química , Benzoxepinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Modelos Moleculares , Estrutura Molecular , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo
20.
J Enzyme Inhib Med Chem ; 23(5): 668-85, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18821256

RESUMO

A series of novel beta-lactam containing compounds are described as antiproliferative agents and potential selective modulators of the oestrogen receptor. The purpose of the study is to evaluate the antiproliferative effects of these compounds on human MCF-7 and MDA MB-231 breast cancer cells. The compounds are designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (beta-lactam), thus providing conformationally restrained analogues of the triarylethylene arrangement exemplified in the tamoxifen type structure. The compounds demonstrated potency in antiproliferative assays against MCF-7 human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the oestrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the beta-lactam products was explored and a brief computational structure-activity relationship investigation with molecular simulation was investigated.


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , beta-Lactamas/síntese química , beta-Lactamas/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Conformação Molecular , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade
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