Die Apoptose von Krebszellen ist die Folge, wenn Epothilone wie Patupilon nach einem bislang unbekannten Mechanismus die Polymerisation von αβ‐Tubulindimeren zu Mikrotubuli auslösen. Durch ...Festkörper‐NMR‐Spektroskopie von Mikrotubuli‐gebundenem Patupilon wurden nun Atompositionen des Wirkstoffs identifiziert, deren chemische Verschiebungen durch den Bindevorgang deutlich verändert werden (siehe Korrelationsspektren von freiem (schwarz) und komplexiertem Patupilon (rot)).
Nicht ganz natürlich: Die „Azathilone“ 1 a und 1 b sind „nicht‐natürliche Naturstoffe“, die sich durch C→N‐Austausch an Position 12 von natürlichen Epothilonen ableiten. Sie sind hochpotente ...Induktoren der Tubulin‐Polymerisation (Bild: Teil eines Mikrotubulus) und hemmen in vitro das Krebszellwachstum. 1 a und 1 b sind Vertreter eines neuen strukturellen Grundgerüsts zur Stabilisierung von Mikrotubuli und vielversprechende Leitstrukturen in der Krebsmittelforschung.
Aktiv wenn gebunden: Die Struktur des Titelsystems in Lösung wurde aus transferierten NOE‐Daten bestimmt (siehe Bild; blau N, rot O, gelb S, grün C), und diese bioaktive Konformation wird mit der ...ungebundenen Konformation verglichen. Interligand‐NOEs, wie sie zwischen Epothilon A und Tubulysin A in Gegenwart von Tubulin beobachtet werden, geben Aufschluss über die Bindungsstelle am Tubulin.
S povećanjem broja korisnika pokretne telefonije raste zabrinutost zbog mogućega štetnog djelovanja radiofrekventnoga mikrovalnog zračenja (RF/MW) na zdravlje čovjeka. Posebno su važni netermalni ...učinci koji nastaju zbog izlaganja RF/MW zračenju koje ne izaziva porast temperature ciljnog tkiva i/ili stanice ili je taj porast neznatan. Mogući biološki učinci takvog zračenja nedovoljno su istraženi. Brojna in vitro istraživanja pokazala su da RF/MW zračenje, čak i unutar dopuštene razine izlaganja, mogu djelovati na staničnu membranu, aktivnost gena, programiranu staničnu smrt, a može uzrokovati i stanični stres. Međutim, učinci RF/MW na neke stanične strukture još su gotovo potpuno nepoznati. Tako je učinak zračenja na citoskelet, koji je funkcionalni i strukturalni dio stanice, slabo istražen. Citoskelet je sastavljen od aktina, intermedijalnih filamenata i mikrotubula. Uloga mikrotubula leži u upravljanju rasporedom staničnih organela, određivanju oblika i polarnosti stanice te vođenju procesa razdvajanja sestrinskih kromatida tijekom somatske diobe stanice, tj. mitoze.
The effects of oryzalin, a dinitroaniline herbicide, on chromosome behavior and on cellular microtubules (MTs) were examined by light microscopy and immunogold staining, respectively, in endosperm ...cells from Haemanthus katherinae Bak. Brief treatments with 1.0·10-8 M oryzalin reduced markedly the migration rate of anaphase chromosomes and 1.0·10-7 M oryzalin stopped migration abruptly. Oryzalin (1.0·10-7 M) depolymerized MTs and prevented the polymerization of new MTs at all stages of the mitotic cycle. The chromosome condensation cycle was unaffected by oryzalin. Endothelial cells from the heart of Xenopus leavis showed no chromosomal or microtubular rearrangements after oryzalin treatment. The inhibition by oryzalin of the polymerization of tubulin isolated from cultured cells of Rosa sp. cv. Paul's scarlet was examined in vitro by turbidimetry, electron microscopy and polymer sedimentation analysis. Oryzalin inhibited the rapid phase of taxol-induced polymerization of rose MTs at 24° C with an apparent inhibition constant (Ki) of 2.59·106 M. Shorter and fewer MTs were formed with increasing oryzalin concentrations, and maximum inhibition of taxol-induced polymerization occurred at approx. 1:1 molar ratios of oryzalin and tubulin. Oryzalin partially depolymerized taxol-stabilized rose MTs. Ligand-binding experiments with 14Coryzalin demonstrated the formation of a tubulin-oryzalin complex that was time- and pH-dependent. The tubulin-oryzalin interaction (24° C, pH 7.1) had an apparent affinity constant (Kapp) of 1.19·105 M-1. Oryzalin did not inhibit taxol-induced polymerization of bovinebrain MTs and no appreciable binding of oryzalin to brain tubulin or other proteins was detected. The results demonstrate pharmacological differences between plant and animal tubulins and indicate that the most sensitive mode of action of the dinitroaniline herbicides is the direct poisoning of MT dynamics in cells of higher plants.
