RESUMO
There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias da Próstata , Proteína de Ligação a Elemento Regulador de Esterol 2 , Masculino , Humanos , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Esteróis/farmacologia , Sinergismo Farmacológico , Camundongos Nus , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Morte Celular/efeitos dos fármacosRESUMO
Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4 ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB4 in 25 % overall yield in just 10â steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4 , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.
Assuntos
Lipoxinas , Doenças Neuroinflamatórias , Eicosanoides , Humanos , Lipoxinas/metabolismoRESUMO
Alzheimer's disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no "curative" disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets.
Assuntos
Doença de Alzheimer , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , HumanosRESUMO
Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.
RESUMO
The discovery of two quinazolinones with selective, single-digit micromolar activity (IC50â¯=â¯6-7⯵M) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites.
Assuntos
Antiprotozoários/farmacologia , Quinazolinonas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinazolinonas/síntese química , Quinazolinonas/química , Pele/citologia , Pele/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The isolation of three new secondary metabolites from the fruiting body of Xylaria polymorpha is described. The new compounds are of mixed biosynthetic origin consisting of a polyketide starter, extended with a methyl orsellinate unit and terminated hydrolytically or with an amine-containing terminal unit.
Assuntos
Policetídeos/isolamento & purificação , Xylariales/química , Endófitos/química , Carpóforos/química , Estrutura Molecular , OntárioRESUMO
The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed structure-activity relationship (SAR) generation revealing synergistic structural features required for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir against acute HSV-1 infections in neurons and minimal toxicity to the host.
Assuntos
Herpesvirus Humano 1/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Aciclovir/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Avaliação Pré-Clínica de Medicamentos , Humanos , Relação Estrutura-Atividade , Células VeroRESUMO
Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.
Assuntos
Antivirais/toxicidade , Avaliação Pré-Clínica de Medicamentos , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Aciclovir/toxicidade , Animais , Sistema Nervoso Central/efeitos dos fármacos , Chlorocebus aethiops , Farmacorresistência Viral/efeitos dos fármacos , Herpes Simples/virologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Células-Tronco Pluripotentes/efeitos dos fármacos , Células Vero/efeitos dos fármacosRESUMO
A novel method for the preparation of 2-carboxyl-3-aryl quinoline derivatives from anilines, ethyl glyoxalate and enol ethers as phenylacetaldehyde surrogates is reported. The three-component coupling reaction occurs rapidly under mild conditions in dichloromethane catalysed by TFA. The method allows a more direct access to 3-aryl quinolines, sidestepping issues encountered with phenylacetaldehyde derivatives. This chemistry was used to prepare quinolines with 3-diarylether functionality that showed low micromolar efficacy (IC50 range: 5-26 µM) against in vitro Toxoplasma gondii coupled with little or no cytotoxicity (TD50≥ 320 µM) towards the host cells.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Éteres/química , Quinolinas/síntese química , Quinolinas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/química , Catálise , Técnicas de Química Sintética , Glioxilatos/química , Quinolinas/químicaRESUMO
We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.
RESUMO
Bioisosteric replacement of cyclic ketone functionality with aryl halides was investigated on a centrally-flexible, five-component 1,2,3-triazole-containing pharmacophore, resulting in enhanced inhibition of aromatase (CYP450 19A1). Structure-activity data generated from both syn- and anti-aldol precursors provides significant insights into the requirements for enhanced potency, validating this novel ketone-to-aryl halide bioisostere hypothesis.
Assuntos
Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Derivados de Benzeno/química , Hidrocarbonetos Halogenados/química , Cetonas/química , Derivados de Benzeno/farmacologia , Neoplasias da Mama/enzimologia , Feminino , Humanos , Hidrocarbonetos Halogenados/farmacologia , Isomerismo , Cetonas/farmacologia , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an initial aldol reaction of a phenylacetate derivative with an aromatic aldehyde. Structure-activity data generated from both syn- and anti-aldol adducts provides initial insights into the requirements for both potency and selectivity.