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“Dimer compounds” derived from natural products. The importance of in vitro stability for the understanding biological activity

Abstract A frequently overlooked issue when assessing the biological properties of novel small molecules, notably natural products, is their stability when exposed to in vitro assay conditions and xenobiotic metabolism. We have been investigating the biological properties of two groups of compounds and assessing their stability in vitro. The lignans, a group of naturally occurring compounds, are phenyl propanoid dimers reported to have a wide variety of biological properties including cholesterol reduction and anticancer effects. We have prepared a series of catechol and phenol lignan analogs and determined that catechol containing lignans are unstable in pH 7.4 phosphate buffer, and both catechol and phenol containing lignans undergo in vitro metabolism to reactive intermediates and Phase 2 conjugates, or both. These processes may have a profound effect on biological activity. We have also prepared a series of novel dimers composed of caffeine linked to caffeine, nicotine, aminoindane or metformin and assessed their ability to interact with α-synuclein, a peptide associated with Parkinson’s disease pathophysiology. The stability of these dimers in vitro will be an important first step to further developing these compounds for the study of Parkinson’s disease