Structural modification of xanthohumol C and the effect on inducing differentiation in neural precursor cells

Destructive diseases concerning the nervous system are an increasing burden in our aging society. After the dogma of the non-regenerating nervous system had to be dropped, a new therapeutic approach arose – the regeneration strategy. In an optimal way, endogenous regeneration could be induced by small molecules using stimulation of differentiation of neural stem cells, without an invasive intervention.

Recently a pyranoflavonoid of Humulus lupulus L. was identified as potent inducer of differentiation in neuronal precursor cells [1]. To quantify the activity, a dual luciferase reporter gene assay based on doublecortin, a marker of early neurons, was used. The most active compound was the pyranochalcone, xanthohumol C.

Accordingly, we questioned if this compound can be used as lead structure for a further development in a regeneration approach. Hence, we compared side-chain open (prenylflavonoids) with side-chain closed flavonoids (pyranoflavonoids) which led to the assumption, that the pyrano ring is one structural characteristic beneficial for differentiation induction.

Consequently, the next step concerning a lead structure was the variation of the chromene structure. Firstly, the chain length of alky substituent and the degree of saturation was modified. Secondly, the oxygen in the pyrano ring was replaced by hetero atoms like sulfur or nitrogen, to reach a different chemical surrounding.

While the side chain prolongation caused a significant loss in activity, the level of activity wasn't changed by the saturation of the chromene system compared to xanthohumol C.

References:

[1] Oberbauer E, Urmann C, Steffenhagen C, Bieler L, Brunner D, Furtner T, Humpel C, Baeumer B, Bandtlow C, Couillard-Després S, Rivera F, Riepl H, Aigner L: Chroman-like Cyclic Prenylflavonoids Promote Neuronal Differentiation and Neurite Outgrowth and are Neuroprotective; J Nut Biochem; 24: 1953 – 62