Neuroregenerative Potential of Prenyl- and Pyranochalcones: A Structure-Activity Study.

Loss of neuronal tissue is a hallmark of age-related neurodegenerative diseases. Since adult neurogenesis has been confirmed in the human brain, great interest has arisen in substances stimulating the endogenous neuronal regeneration mechanism based on adult neural stem cells. Medicinal plants are a valuable source of neuroactive small molecules. In the structure-activity study presented here, the activities of prenyl- and pyranochalcones were compared to each other, using a differentiation assay based on the doublecortin promoter sequences. The latter revealed that the pyrano ring is a crucial structural element for the induction of neuronal differentiation of adult neural stem cells, while compounds with a prenyl group show significantly lower activities. Furthermore, a decrease of pro-differentiation activity was observed following structural modifications, such as substitutions on the pyrano ring and on the B-ring of the chalcone. We also initiated the elucidation of the structural characteristics of the newly discovered lead substance xanthohumol C, which correlated with the activation of the doublecortin promoter during neuronal differentiation.

Synthesis of demethylxanthohumol, a new potent apoptosis-inducing agent from hops.

Starting from commercially available phloracetophenone (= 1-(2,4,6-trihydroxyphenyl)ethanone), we synthesized demethylxanthohumol (4), a derivative of xanthohumol, devoid of 6'-O-methyl group. Both are prenylchalcones derived from hops (Humulus lupulus). The synthesis was accomplished by an aldol condensation between MOM-protected acetophenone 2 and MOM-protected benzaldehyde 3. The resulting demethylxanthohumol (4) displayed antiproliferative properties. Demethylxanthohumol (4) induced also apoptosis via the mitochondrial pathway in BJAB cells (Burkitt lymphoma cell line) and in primary lymphoblasts of childhood acute lymphoblastic leukemia (ALL).

Ability of prenylflavanones present in hops to induce apoptosis in a human Burkitt lymphoma cell line.

The identification of effective cancer preventive compounds from hops has become an important issue in public health-related research. We compared the antiproliferative and apoptosis-inducing effects of side chain variants of prenylflavanones, e. g., 8-prenylnaringenin (7) and 8-geranylnaringenin (10), which have been identified in hops (Humulus lupulus), and their synthetic variations 8-furanmethylnaringenin (8) and 8-cinnamylnaringenin (9). These were accessible by a Mitsunobu reaction and Claisen rearrangement. Flavanones 9 and 10 showed cytotoxic and apoptotic activities. Apoptosis was induced in a mitochondrial dependent manner. 8-Cinnamylnaringenin (9) displayed noticeably improved apoptotic effects when compared to 8-prenylnaringenin. The potential of 8-prenylnaringenin (7) is shown in an ex vivo experiment on a multi-drug resistant leukaemia blast.