RESUMEN
A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (1, 16-oxo-ent-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure-activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents.
Asunto(s)
Antimitóticos/síntesis química , Antimitóticos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/farmacología , Erizos de Mar/efectos de los fármacos , Animales , Antimitóticos/química , Antineoplásicos/química , Cationes/química , Modelos Animales de Enfermedad , Diterpenos/química , Diterpenos de Tipo Kaurano/síntesis química , Humanos , Mar Mediterráneo , Mitocondrias/efectos de los fármacos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Compuestos Organofosforados/química , Relación Estructura-ActividadRESUMEN
New derivatives of steviol 1, the aglycone of the glycosides of Stevia rebaudiana, including a novel class of semisynthetic diterpenoids, namely macrocyclic ent-kauranes were synthesized. These compounds possess antituberculosis activity inhibiting the in vitro growth of Mycobacterium Tuberculosis (H37R(V) strain) with MIC 5-20 µg/ml that is close to MIC 1 µg/ml demonstrated by antituberculosis drug isoniazid in control experiment. For the first time it was found that the change of ent-kaurane geometry (as in steviol 1) of tetracyclic diterpenoid skeleton to ent-beyerane one (as in isosteviol 2) influences on antituberculosis activity.
Asunto(s)
Antituberculosos/síntesis química , Diterpenos de Tipo Kaurano/química , Compuestos Macrocíclicos/química , Antituberculosos/química , Antituberculosos/farmacología , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Stevia/químicaRESUMEN
The present work highlights the key aspects of the influence of calix[4]arene and tetrathiacalix[4]arene scaffolds on the structural and photophysical properties of Tb3+ complexes with tetra-1,3-diketone derivatives of the macrocycles in DMF solutions. The equilibrium forms of Tb3+ complexes with unsubstituted and functionalized by acetylacetonyl groups at the upper rim of calix[4]arenes and thiacalix[4]arenes are revealed from UV-, NMR, MALDI TOF mass spectroscopy, quantum-chemical calculations at the DFT level and luminescence spectroscopy data. In alkaline DMF solutions, the ligands form predominantly 1 : 1 complexes with Tb3+ ions. However, the replacement of a calix[4]arene-scaffold by a thiacalix[4]arene-scaffold in the tetra-1,3-diketone derivatives shifts the equilibrium forms of Tb3+ complexes from monomeric to the dimeric ones. DFT calculations in combination with experimental data reveal the most reliable structures of complexes. The quantitative analysis of the photophysical parameters in correlation with the structural features of the complexes highlights the specific inner-sphere environment of Tb3+ ions in the dimeric complexes with the thiacalix[4]arene derivatives as a reason for greater sensitization of Tb3+-centered luminescence.