RESUMO
Organic isothiocyanates (ITCs) are a class of anticancer agents which naturally result from the enzymatic degradation of glucosinolates produced by Brassica vegetables. Previous studies have demonstrated that the structure of an ITC impacts its potency and mode(s) of anticancer properties, opening the way to preparation and evaluation of synthetic, non-natural ITC analogues. This study describes the preparation of a library of 79 non-natural ITC analogues intended to probe further structure-activity relationships for aryl ITCs and second-generation, functionalized biaryl ITC variants. ITC candidates were subjected to bifurcated evaluation of antiproliferative and antioxidant response element (ARE)-induction capacity against human MCF-7 cells. The results of this study led to the identification of (1) several key structure-activity relationships and (2) lead ITCs demonstrating potent antiproliferative properties.
Assuntos
Antineoplásicos , Isotiocianatos , Antineoplásicos/farmacologia , Elementos de Resposta Antioxidante , Humanos , Isotiocianatos/química , Células MCF-7 , Relação Estrutura-AtividadeRESUMO
The consumption of Brassica vegetables provides beneficial effects through organic isothiocyanates (ITCs), products of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC l-sulforaphane (l-SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the anticancer properties of ITCs like l-SFN have been extensively studied and l-SFN has been the subject of multiple human clinical trials, the scope of this work has largely been limited to those derivatives found in nature. Previous studies have demonstrated that structural changes in an ITC can lead to marked differences in a compound's potency to 1)â inhibit the growth of cancer cells, and 2)â alter cellular transcriptional profiles. This study describes the preparation of a library of non-natural aryl ITCs and the development of a bifurcated screening approach to evaluate the dose- and time-dependence on antiproliferative and chemopreventive properties against human MCF-7 breast cancer cells. Antiproliferative effects were evaluated using a commercial MTS cell viability assay. Chemopreventive properties were evaluated using an antioxidant response element (ARE)-promoted luciferase reporter assay. The results of this study have led to the identification of 1)â several key structure-activity relationships and 2)â lead ITCs for continued development.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Isotiocianatos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Elementos de Resposta Antioxidante/genética , Antioxidantes/síntese química , Antioxidantes/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Expressão Gênica/efeitos dos fármacos , Humanos , Isotiocianatos/síntese química , Isotiocianatos/química , Células MCF-7 , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
The natural products novobiocin and derrubone have both demonstrated Hsp90 inhibition and structure-activity relationships have been established for each scaffold. Given these compounds share several key structural features, we hypothesized that incorporation of elements from each could provide insight to structural features important for Hsp90 inhibition. Thus, chimeric analogues of novobiocin and derrubone were constructed and evaluated. These studies confirmed that the functionality present at the 3-position of the isoflavone plays a critical role in determining Hsp90 inhibition and suggests that the bicyclic ring system present in both novobiocin and derrubone do not share similar modes of binding.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Isoflavonas/química , Isoflavonas/farmacologia , Novobiocina/química , Novobiocina/farmacologia , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Flavonas/síntese química , Flavonas/química , Flavonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isoflavonas/síntese química , Estrutura Molecular , Novobiocina/síntese químicaRESUMO
Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90 C-terminus and induces degradation of Hsp90-dependent client proteins at approximately 700 microM in breast cancer cells (SKBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species exhibit antiproliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated to elucidate structure-activity relationships for novobiocin as an anticancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines.
Assuntos
Cumarínicos/química , Desenho de Fármacos , Novobiocina/síntese química , Novobiocina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Naftalenos/química , Novobiocina/química , Quinolinas/químicaRESUMO
Isothiocyanates (ITCs) are one of the many classes of breakdown products of glucosinolates found in crucifers such as broccoli and are thought to be partially responsible for the reduced risk of degenerative diseases associated with the consumption of vegetables. The production of ITCs such as L-sulforaphane is dependent on the hydrolytic bioactivities of myrosinase, localized both within vegetable tissues and within flora of the human GI tract, and is associated with important cancer chemopreventive activities. We hypothesized that novel isothiocyanates with enhanced chemopreventive properties relative to L-sulforaphane could be identified and that their glucosinolate precursors could be synthesized. From a library of 30 synthetic ITCs, we identified several with bioactivities equal or superior to those of L-sulforaphane. The corresponding non-natural glucosinolate precursors to these novel ITCs were constructed and found to be substrates for myrosinase. By utilizing a novel RP-HPLC assay to monitor myrosinase-dependent hydrolysis reactions, 2,2-diphenylethyl glucosinolate and (biphenyl-2-yl)methyl glucosinolate were shown to exhibit 26.5 and 2.8 %, respectively, of the relative activity of sinigrin and produced their corresponding ITCs in varying yields. These data support the notion that non-natural glucosinolates can act as prodrugs for novel ITCs, with a mechanism of action reliant on their hydrolytic cleavage by myrosinase. Such non-natural glucosinolates may serve as very economical chemopreventive agents for individuals at risk for cancers of and around the GI tract.
Assuntos
Carcinoma/tratamento farmacológico , Glucosinolatos/química , Glicosídeo Hidrolases/química , Isotiocianatos/química , Isotiocianatos/síntese química , Tiocianatos/química , Tiocianatos/síntese química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioprevenção , Cromatografia Líquida de Alta Pressão/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais/efeitos dos fármacos , Glucosinolatos/síntese química , Glucosinolatos/farmacologia , Humanos , Hidrólise , Isotiocianatos/farmacologia , Camundongos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Sulfóxidos , Tiocianatos/farmacologia , Fatores de Tempo , Água/químicaRESUMO
FK-228 is a potent histone deacetylase (HDAC) inhibitor with tremendous therapeutic potential against a wide array of human cancers. We describe the development of analogs that share FK-228's novel mechanism of activation and HDAC inhibition.