Methylene-cycloalkylacetate (MCA) scaffold-based compounds as novel neurotropic agents

Tricyclic spiroether structures can frequently be observed as scaffold segments of various biochemical compounds and drugs of natural origins. Examples of these structures have been identified among carbohydrates, terpenoids and alkaloids. Unfortunately, access to a large number of these target molecules and their structural analogues is either unknown or hindered by their multistep syntheses.

We realized that most of the tricyclic spiranoid ethers might be derived from a simple and common collective precursor via a controlled intramolecular sequence of transformations. We discovered that monocyclic diene-alcohol precursor (see scheme) could serve as such building block for their synthesis via controlled Pd-catalyzed cascade cyclization reactions. We demonstrated, for the first time, a simple link between diene-alcohol cores and diverse medium-sized spiroether architectures.

We have also noticed that precursors, employed as a platform for syntheses of spiroethers, possess the capacity to act as standalone cores of numerous natural products (such as dysidolide, halmic acid, angolensate and others). Our study, therefore, was inspired by the assumption that synthetic diene-alcohol scaffolds, which are small, rigid, and highly reminiscent of natural scaffolds, could serve as operational ligands for development of a neurotropic lead compound. Many diene-alcohol-based natural products have been firmly established to demonstrate pharmacological activities. Thus, we were motivated to apply our designed architectures to the discovery of novel neurotropic compounds using the pheochromocytoma (PC12) cell neuronal model. We investigated the neurotropic effect of a broad library of diene-alcohol and other related derivatives by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by using a light microscope camera, and digitized photographs were analyzed for compound-induced neurotropic activity using an NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. By employing this line of research, our ultimate aim is to single out a small molecules, bearing potential for treatment of brain disorders, caused by insufficient trophic support.