Sew simple: How can you put a molecular bead on a thread when no recognition elements exist between them? A mechanically interlocking auxiliary assembles the macrocycle around a template, controlled submolecular translation moves the ring over the desired substrate and, finally, cleavage of the auxiliary leaves an apparently “impossible” rotaxane (see scheme).
Tumor hypoxia provides a key difference between healthy and cancerous cells. It can be exploited to produce drug selectivity, offering a reductase-rich environment for prodrug activation. Nitrogen mustard drugs are cytotoxic, but usually unselective. Polyamine mustards are candidates for conversion into hypoxia-selective prodrugs via complexation with metals. Reduction to a less stable complex can free the active drug. The novel Cu(II) complexes of N-mustard derivatives of 1,4,7-triazacyclononane (tacn), 1,4,7,10-tetraazacyclododecane (cyclen), and 1,4,8,11-tetraazacyclotetradecane (cyclam) were assessed in vitro as hypoxia-selective cytotoxins. The cyclen mustard complex showed 24-fold selectivity as a hypoxia-selective bioreductive prodrug, with an IC50 value of 2 microM against the lung tumor cell line A549. Reversible redox behavior and stability of the cyclen-Cu(II) complex in aqueous solution correlated with good hypoxia selectivity. The two other related complexes showed irreversible redox behavior and low aqueous stability and were not hypoxia-selective. The use of macrocyclic nitrogen mustard complexes represents a promising new strategy in the design of hypoxia-selective cytotoxins.
Geschickt eingefädelt: Keine Erkennung zwischen den Komponenten ist für das hier beschriebene molekulare Einfädeln nötig. Ein Auxiliar fixiert den Makrocyclus in einer geeigneten Position, sodass der Ring in einer kontrollierten submolekularen Bewegung über die Alkylkette des Substrats schlüpfen kann. Die Abspaltung des Auxiliars führt schließlich zu einem scheinbar „unmöglichen“ Rotaxan (siehe Schema).
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