Hybrid Molecules Incorporating Natural Products: Applications in Cancer Therapy, Neurodegenerative Disorders and Beyond

In this article the design of hybrid molecules that covalently connect two distinct drug entities in one molecule, at least one part being a biologically active natural product will be discussed. In the quest for novel drug entities, the hybrid approach is a promising path to drug molecules that can effectively target multifactorial diseases including neurodegenerative disorders like Alzheimer's and Parkinson's diseases (AD and PD). The hybrid approach can also be used to optimize certain biological properties like affinity and selectivity, but also to gain novel biological activities distinct from the ones of the components. Due to the high potential of natural products to exhibit pronounced biological activities, natural products have been one of the major sources of components in hybrid molecules. This review will cover their applications in developing drugs for neurodegenerative disorders, in the diverse field of anti-cancer agents (which represents the major application for natural products in medicinal chemistry), but also in miscellaneous areas of bioactive compounds including antioxidants, antimalarial drugs and estrogen-related hybrids to reach various therapeutic aims. The unique tasks of hybrid molecule design will be addressed, such as describing suitable ways to chemically connect the drug components, how to use the approach to enhance biological activity with respect to both activity and selectivity and potential drawbacks of the hybrid approach. It will be shown that hybrids can be more than the sum of their components, but in many cases should be considered as pharmacological entities in their own respect.