RESUMO
Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Iodados/síntese química , Hidrocarbonetos Iodados/farmacologia , Compostos Organofosforados/síntese química , Pró-Fármacos/síntese química , Estilbenos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Criança , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hidrocarbonetos Iodados/química , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Estilbenos/química , Estilbenos/farmacologiaRESUMO
Marine Natural Products (MNPs), such as bryostatin 1, are exposed to a range of physical and chemical conditions through the life cycle of the host organism. These include exposure to sunlight, oxidizing and reducing agents, cation binding, and adsorption to reactive metal oxide surfaces. Using Fourier Transform-Ion Cyclotron Resonance (FT-ICR), Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS), UV/Vis absorbance spectroscopy, and molecular modeling, we studied the impact of UV light, TiO2, I2, and reaction with FeCl3 on the structure of bryostatin 1. Our results demonstrate that natural conditions transform bryostatin to a number of structures, including one with a molar mass of 806 Da, which we have previously identified in the sediment collected from the Gulf of Mexico. To date, at least 20 different structures of bryostatin have been reported in the literature. This work suggests that these variations may be products of the chemical environment in which the bryozoa Bugula neritina resides and are not the result of genetic variations within Bugula.