RESUMO
The title compound, C(40)H(16)O(4) or [C(10)H(4)O](4), is a planar tetrameric cyclooligomer which crystallizes in the monoclinic space group P2(1)/n. The compound is located on an inversion center with the asymmetric unit consisting of half of the molecule. The compound displays an interesting packing structure, where the cyclooligomer displays both layered packing with respect to nearest neighbors and a rotation of adjacent planar rings that results in additional interactions. The geometric parameters of the compound agree well with those of comparable cyclooligomers, while the packing reveals some similarities and differences.
RESUMO
Prenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation, but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation. The combination treatment results in a G(0)/G(1) arrest and synergistic inhibition of proliferation of cultured STS-26T malignant peripheral nerve sheath tumor cells. We also show that the antiproliferative activity of drugs in combination occurs in the context of autophagy. The combination treatment also induces autophagy in the MCF10.DCIS model of human breast ductal carcinoma in situ and in 1c1c7 murine hepatoma cells, where it also reduces proliferation. At the same time, there is no detectable toxicity in normal immortalized Schwann cells. These studies establish GGTI-2Z as a novel geranylgeranyl pyrophosphate derivative that may work through a new mechanism involving the induction of autophagy and, in combination with lovastatin, may serve as a valuable paradigm for developing more effective strategies in this class of antitumor therapeutics.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Autofagia , Diterpenos/farmacologia , Lovastatina/farmacologia , Compostos Organofosforados/farmacologia , Transferases/antagonistas & inibidores , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Fase G1/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Humanos , Camundongos , Prenilação de Proteína , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacosRESUMO
Neurofibromatosis type 1 (NF1) is a genetic disorder that is driven by the loss of neurofibromin (Nf) protein function. Nf contains a Ras-GTPase-activating protein domain, which directly regulates Ras signaling. Numerous clinical manifestations are associated with the loss of Nf and increased Ras activity. Ras proteins must be prenylated to traffic and functionally localize with target membranes. Hence, Ras is a potential therapeutic target for treating NF1. We have tested the efficacy of two novel farnesyl transferase inhibitors (FTIs), 1 and 2, alone or in combination with lovastatin, on two NF1 malignant peripheral nerve sheath tumor (MPNST) cell lines, NF90-8 and ST88-14. Single treatments of 1, 2, or lovastatin had no effect on Ras prenylation or MPNST cell proliferation. However, low micromolar combinations of 1 or 2 with lovastatin (FTI/lovastatin) reduced Ras prenylation in both MPNST cell lines. Furthermore, this FTI/lovastatin combination treatment reduced cell proliferation and induced an apoptotic response as shown by morphological analysis, procaspase-3/-7 activation, loss of mitochondrial membrane potential, and accumulation of cells with sub-G(1) DNA content. Little to no detectable toxicity was observed in normal rat Schwann cells following FTI/lovastatin combination treatment. These data support the hypothesis that combination FTI plus lovastatin therapy may be a potential treatment for NF1 MPNSTs.
Assuntos
Apoptose/efeitos dos fármacos , Farnesiltranstransferase/antagonistas & inibidores , Lovastatina/administração & dosagem , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/patologia , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/patologia , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Farnesiltranstransferase/metabolismo , Lovastatina/química , Neurofibromatose 1/enzimologia , Ratos , Ratos Sprague-DawleyRESUMO
[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.
Assuntos
Alcenos/síntese química , Alcinos/síntese química , Muramidase/química , Fármacos Fotossensibilizantes/síntese química , Receptores de Estrogênio/química , Soroalbumina Bovina/química , Alcenos/química , Alcenos/efeitos da radiação , Alcinos/química , Alcinos/efeitos da radiação , Animais , Sítios de Ligação , Bovinos , Humanos , Estrutura Molecular , Muramidase/metabolismo , Fotoquímica , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Receptores de Estrogênio/metabolismo , Soroalbumina Bovina/metabolismo , Relação Estrutura-AtividadeRESUMO
A designed molecule with capacity to alkylate DNA bulges has been prepared from readily available starting materials. The spirocyclic template utilized was designed on the basis of established architectures, and equipped with a mustard alkylating group. Preliminary studies confirm alkylation of specific bulged sequences, paving the way for second generation substrates with higher affinity.
Assuntos
Alquilantes/síntese química , DNA/genética , DNA/metabolismo , Conformação de Ácido Nucleico , Alquilantes/metabolismo , Sequência de Bases/fisiologia , Sítios de Ligação/fisiologiaRESUMO
A series of photoactivated enediynes was prepared, and successfully employed for the selective degradation of target proteins.
Assuntos
Oligossacarídeos/síntese química , Oligossacarídeos/farmacologia , Proteínas/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Dano ao DNA/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Histonas/química , Histonas/efeitos dos fármacos , Indicadores e Reagentes , Fotoquímica , Proteínas/química , Soroalbumina Bovina/química , Soroalbumina Bovina/efeitos dos fármacosRESUMO
Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.