Jens Hasserodt

Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death

Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introduce the photostatins, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics. Photostatins modulate microtubule dynamics with a subsecond response time and control mitosis in living organisms with single-cell spatial precision. In longer-term applications in cell culture, photostatins are up to 250 times more cytotoxic when switched on with blue light than when kept in the dark. Therefore, photostatins are both valuable tools for cell biology, and are promising as a new class of precision chemotherapeutics whose toxicity may be spatiotemporally constrained using light.

Bispidine Platform Grants Full Control over Magnetic State of Ferrous Chelates in Water

A bicyclic ligand platform for iron(II), which allows total control over the complexs magnetic properties in aqueous solution simply by varying one of the six coordination sites of the bispidine ligand, is reported. To achieve this, an efficient synthetic route to an N5 bispidine framework (ligand L4) that features an unsubstituted N-7 site is established. Then, by choosing appropriate N-7-coordinating substituents, the spin state of choice can be imposed on the corresponding ferrous complexes under environmentally relevant conditions in water and near-room temperature. Importantly, the first low-spin and diamagnetic iron(II) chelates in the bispidine series, both in the solid state and in aqueous solution, are reported. The eradication of head-on steric clashes between pendent coordinating arms is at the origin of this success. A new pair of constitutionally similar ferrous coordination compounds of a multidentate ligand system is obtained, which exhibits a distinctly binary (off-on) magnetic relationship. The new synthetic intermediate L4 may be substituted in just one step by any desired pendent arm, thus allowing access to complexes with finely tuned magnetic properties.

Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen

Cladistic analysis allows inference of the structure of an ancestral steroid that acts as a ligand for the ancestral receptor. The origin of ancient ligand/receptor couples is often analyzed via reconstruction of ancient receptors and, when ligands are products of metabolic pathways, they are not supposed to evolve. However, because metabolic pathways are inherited by descent with modification, their structure can be compared using cladistic analysis. Using this approach, we studied the evolution of steroid hormones. We show that side-chain cleavage is common to most vertebrate steroids, whereas aromatization was co-opted for estrogen synthesis from a more ancient pathway. The ancestral products of aromatic activity were aromatized steroids with a side chain, which we named “paraestrols.” We synthesized paraestrol A and show that it effectively binds and activates the ancestral steroid receptor. Our study opens the way to comparative studies of biologically active small molecules.

3,5,7-Tripropyl-1-aza-adamantane-4,6,10-triol.

The title compound, C18H33NO3, was prepared according to a highly diastereoselective hydrogenation procedure from 3,5,7-triallyl-1-azaadamantane-4,6,10-trione. The crystal structure of the title compound contains two crystallographically independent molecules (Z′ = 2), which are linked by intermolecular hydrogen bonding into chains. In contrast to the azaadamantanones, the azaadamantanetriol core of the title compound does not show any particular C—C bond elongation.