Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project.

Neurodegenerative Erkrankungen und Rückenmarksverletzungen betreffen weltweit etwa 50 Millionen Menschen und verursachen Gesundheitskosten von insgesamt mehr als 600 Milliarden Dollar pro Jahr. Nervenwachstumsfaktoren, d. h. Neurotrophine, sind potenzielle Therapeutika für diese Erkrankungen, denn sie können die Regeneration von Nerven fördern. Durchschnittlich 500 Publikationen jährlich belegen die Bedeutung der Neurotrophine in den biomedizinischen Wissenschaften und ihr Potenzial für therapeutische Anwendungen. Allerdings ist die klinische Verwendung von Neurotrophinen wegen ihres schlechten pharmakokinetischen Profils stark eingeschränkt. Niedermolekulare Verbindungen, die die neurotrophe Aktivität modulieren, bieten hingegen einen vielversprechenden Therapieansatz bei neurologischen Erkrankungen. Die Natur hat für eine beeindruckende Zahl von Naturstoffen mit starken neurotrophen Wirkungen gesorgt. Die aktuellen Strategien zur Synthese dieser Verbindungen sowie deren Fähigkeit, das Wachstum und die Erneuerung von Nervenzellen zu induzieren, bilden den Schwerpunkt dieses Aufsatzes. Es ist davon auszugehen, dass neurotrophe Naturstoffe nicht nur als Leitstrukturen in der Wirkstoffentwicklung genutzt werden können, sondern auch für das nächste große Projekt der Biomedizin: die Kartierung der Hirnaktivität (BAM, Brain Activity Map).

Majucin-type sesquiterpenes from Illicium sp., such as jiadifenolide (2), jiadifenin (3), and (1R,10S)-2-oxo-3,4-dehydroxyneomajucin (4, ODNM), possess a complex caged chemical architecture and remarkable neurotrophic activities. As such, they represent attractive small-molecule leads against various neurodegenerative diseases. We present an efficient, enantioselective, and unified synthesis of 2, 3, and 4 and designed analogues that diverge from tetracyclic key intermediate 7. The synthesis of 7 is highlighted by the use of an enantioselective Robinson annulation reaction (construction of the AB rings), a Pd-mediated carbomethoxylation reaction (construction of the C ring), and a one-pot oxidative reaction cascade (construction of the D ring). Evaluation of the neurotrophic activity of these compounds led to the identification of several highly potent small molecules that significantly enhanced the activity of nerve growth factor (NGF) in PC-12 cells. Moreover, efforts to define the common pharmacophoric motif suggest that substitution at the C-10 center significantly affects bioactivity, while the hemiketal moiety of 2 and 3 and the C-1 substitution might not be critical to the neurotrophic activity.

An efficient formal synthesis of (−)-englerin A (1) is reported. The target molecule is a recently isolated guaiane sesquiterpene that possesses highly potent and selective activity against renal cancer cell-lines. Our enantioselective strategy involved the construction of the BC ring system of compound 1 through a Rh^II-catalyzed [4+3] cycloaddition reaction followed by subsequent attachment of the A ring through an intramolecular aldol condensation reaction. As such, this strategy allows the synthesis of truncated englerins. Evaluation of these analogues with the A498 renal cancer cell-line suggested that the A ring of englerin is crucial to its antiproliferative activity. Moreover, evaluation of these analogues led to the identification of potent growth-inhibitors of CEM cells with GI₅₀ values in the range 1–3 μM.

The natural product gambogic acid (GA) has shown significant potential as an anticancer agent as it is able to induce apoptosis in multiple tumor cell lines, including multidrug-resistant cell lines, as well as displaying antitumor activity in animal models. Despite the fact that GA has entered phase I clinical trials, the primary cellular target and mode of action of this compound remain unclear, although many proteins have been shown to be affected by it. By thorough analysis of several cellular organelles, at both the morphological and functional levels, we demonstrate that the primary effect of GA is at the mitochondria. We found that GA induces mitochondrial damage within minutes of incubation at low-micromolar concentrations. Moreover, a fluorescent derivative of GA was able to localize specifically to the mitochondria and was displaced from these organelles after competition with unlabeled GA. These findings indicate that GA directly targets the mitochondria to induce the intrinsic pathway of apoptosis, and thus represents a new member of the mitocans.

Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70 % of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural-product-based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development.