merrilactone-a and jiadifenin

Neurotrophic factors have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular-weight proteins are unable to cross the blood-brain barrier and are easily decomposed under physiological conditions. Thus, small molecules that can mimic the functions of neurotrophic factors are promising alternatives for the treatment of neurodegenerative disease. Since 1990, the author has been involved in searching for natural products with typical neurotrophic properties that can cause neurogenesis, enhance neurite outgrowth, and protect against neuronal death by using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). Through these research activities on neurotrophic natural products, the author has tried to induce a paradigm shift from the discipline of natural products chemistry to science disciplines. This review focuses on our independent synthetic studies of the neurotrophic natural products discovered in the plants. The following synthetic elaborations are described: syntheses of dimeric isocuparane-type sesquiterpenes mastigophorenes A and B, macrocyclic bis-bibenzyls plagiochins A-D and cavicularin through a Pd-catalyzed Stille-Kelly reaction; the formal synthesis of merrilactone A and jiadifenin, which are seco-prezizaane-type sesquiterpenes, through intramolecular Pd-catalyzed Mizoroki-Heck and Tsuji-Trost reactions; and finally the first enantioselective synthesis of neovibsanin B, a vibsane-type diterpene, through a Pd-catalyzed cyclic carbopalladation-carbonyl tandem reaction.

Topics: Animals; Biological Products; Blood-Brain Barrier; Bridged-Ring Compounds; Cyclopentanes; Diterpenes; Lactones; Mice; Molecular Weight; Nerve Growth Factors; Neurodegenerative Diseases; Organic Chemistry Phenomena; Rats; Sesquiterpenes; Stereoisomerism

The possibility for the application of organic synthesis to the discovery of new agents in combating neurodegenerative disorders is described. Our focus has been on agents derived from natural-product leads and natural products themselves prepared through total synthesis. Herein, we describe some of the chemistry as well as interesting observations made along the way.

Topics: Biological Products; Bridged-Ring Compounds; Dioxoles; Diterpenes; Lactones; Molecular Structure; Neurodegenerative Diseases; Sesquiterpenes; Terpenes; Triterpenes