RESUMO
We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [(3)H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents.
Assuntos
Alcaloides/química , Produtos Biológicos/química , Tubulina (Proteína)/efeitos dos fármacos , Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Colchicina/química , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tubulina (Proteína)/químicaRESUMO
A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Podofilotoxina/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células Jurkat , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Podofilotoxina/síntese química , Podofilotoxina/químicaRESUMO
Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene-phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control.
On a réalisé la synthèse de plusieurs homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine en faisant appel à une stratégie de recyclisation oxydante phenantrènephénathridone. Les étapes clés impliquent la dihydroxylation du bromobenzène, l'addition d'une arylalane à une époxyaziridine, une ouverture intramoléculaire d'aziridine sur gel de silice en phase solide et la stratégie de recyclisation mentionnée plus haut. Les données expérimentales et spectrales sont rapportées pour tous les nouveaux produits. Tous les homologues en C-1 de la pancratistatine et de la 7-désoxypencratistatine ont été évalués pour leur activité à contrer la prolifération dans un éventail de lignées de cellules cancéreuses humaines. Tel que prévu, les composés 7-hydroxy sont les plus puissants alors que l'activité de l'analogue C-1 benzoxyméthyle est supérieure à celle de la narciclasine qui a été utilisée comme contrôle positif.
RESUMO
The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos/farmacologia , Isoquinolinas/farmacologia , Alcaloides de Amaryllidaceae/síntese química , Alcaloides de Amaryllidaceae/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bromobenzenos/química , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; and oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.
Assuntos
Alcaloides de Amaryllidaceae/síntese química , Antineoplásicos Fitogênicos/síntese química , Isoquinolinas/síntese química , Aldeídos/química , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Aziridinas/química , Catálise , Linhagem Celular Tumoral , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/química , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Estrutura Molecular , Oxirredução , Fenantrenos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The mechanisms of invasion and metastasis are poorly understood. Our previous studies demonstrated that cancer cell invasion may result from reorganization of membrane molecules, thereby initiating signaling pathways. To increase our understanding on how cancer cells govern metastases we studied the established LNCaP prostate cancer progression model. Herein we show that the bone metastatic derivative cell line, C4-2B, displays changes in adhesion to collagen type I and invasion into collagen type I. Moreover, we found that these changes were concomitant with activation of the FAK/src/paxillin/Rac/JNK signaling pathway and increased activity of matrix metalloproteinases (MMPs)-2 and -9. Inhibition of src and JNK resulted in inhibition of adhesion and invasion, and deactivation of the signaling molecules in the identified pathway as well as reduced activity of MMPs. Additionally, we found a pivotal role for the integrin alpha2 subunit since lateral redistribution and clustering were responsible for activation of the downstream signaling and function blocking of the integrin alpha2 subunit resulted in poor adhesion and inhibition of invasion. In conclusion, our results suggest that invasion of prostate cancer cells can be ascribed to reorganization and clustering of integrin alpha2 subunits, resulting in activation of associated FAK/src/paxillin/Rac/JNK, leading to increased activity of MMPs and thus invasion.
Assuntos
Adesão Celular , Movimento Celular , Integrina alfa2/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais , Western Blotting , Colágeno Tipo I/metabolismo , Citometria de Fluxo , Imunofluorescência , Quinase 1 de Adesão Focal/metabolismo , Humanos , Imunoprecipitação , MAP Quinase Quinase 4/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica , Paxilina/metabolismo , Fosforilação , Células Tumorais Cultivadas , Proteínas rac de Ligação ao GTP/metabolismo , Quinases da Família src/metabolismoRESUMO
Twenty-nine Amaryllidaceae alkaloids and their derivatives belonging to the five most common groups, including lycorine, lycorenine, tazettine, crinine, and narciclasine types, were evaluated for antiproliferative, apoptosis-inducing, and anti-invasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine, and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis mediated. Thus, apoptosis in Jurkat cells was triggered by narciclasine, narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydronarciclasine, trans-dihydronarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of narciclasine, lycorine, and haemanthamine, the apoptosis-inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent anti-invasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The anti-invasive activity of buphanamine is particularly promising because this alkaloid is not toxic to cells even at much higher doses. This work has resulted in the identification of several novel leads for anticancer drug design.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Leucemia/tratamento farmacológico , Liliaceae/química , Estrutura MolecularRESUMO
Ethnotraditional use of plant-derived natural products plays a significant role in the discovery and development of potential medicinal agents. Plants of the genus Taraxacum, commonly known as dandelions, have a history of use in Chinese, Arabian and Native American traditional medicine, to treat a variety of diseases including cancer. To date, however, very few studies have been reported on the anti-carcinogenic activity of Taraxacum officinale (TO). In the present study, three aqueous extracts were prepared from the mature leaves, flowers and roots, and investigated on tumor progression related processes such as proliferation and invasion. Our results show that the crude extract of dandelion leaf (DLE) decreased the growth of MCF-7/AZ breast cancer cells in an ERK-dependent manner, whereas the aqueous extracts of dandelion flower (DFE) and root (DRE) had no effect on the growth of either cell line. Furthermore, DRE was found to block invasion of MCF-7/AZ breast cancer cells while DLE blocked the invasion of LNCaP prostate cancer cells, into collagen type I. Inhibition of invasion was further evidenced by decreased phosphorylation levels of FAK and src as well as reduced activities of matrix metalloproteinases, MMP-2 and MMP-9. This study provides new scientific data on TO and suggests that TO extracts or individual components present in the extracts may be of value as novel anti-cancer agents.