Molecular, pharmacological and chemical biology of caffeic acid and derivatives

Caffeic acid (CA) is one of the most abundant hydroxycinnamic acids in plants, fruits, coffee, and propolis. CA and its derivative CAPE (CA phenethyl ester) have been well characterized on their aspects of chemistry, biochemistry, immunnopharmacology, molecular biology, and cell biology. During the past two decades, remarkable progress in the potential benefits of CA and CAPE has been documented. CA and its natural derivatives are multi-functional and non-toxic stabilizing compounds, which can thus be salubrious for food additives, cosmetic, drugs, pharmaceutics, and overall well-being. Chemically, they easily chelate cations such as Zn⁺.⁺, Mn⁺⁺, and Fe⁺⁺ and modulate metal enzyme activities such as matrix metalloproteinases. This specific property has been attributed to the anti-angiogenic and tissue remodeling capacities of the compounds. In intracellular signaling pathway, they effectively inhibit the phosphorylation of kinases such as mitogen-activated protein kinase (MAPK) and transcription factors such as nuclear factor-κB (NF-κB), thus contributing to the down-regulation of specific genes and cellular phenotype changes. The cellular regulatory functions have stimulated the researchers to study the pharmacological activities of CA and CAPE. However, there has been no definitive conclusion about how to regulate the cell functions when they initially meet the cells, more specifically how to interact with the cellular receptors or counterparted molecules on the cell surface. CA, as a leader compound, can potentially be applied for new functional and chemotherapeutic agents using fused chemi-biological synthesis in oxidative stressrelated diseases such as inflammation, cell transformation, and degenerative pathology. It is also a candidate for cooperative adjuvant therapy in various human diseases, such as degenerative diseases, inflammatory diseases, and transformed cancer. It is assumed that in contrast to conventional medicines, CA does not have side effects. Understanding the mechanism of the interaction of CA with biological targets at the molecular level will allow researchers to explain its positive effects on human. Chemobiological fusion science, using CA as the chemical scaffold, will construct new drugs for human diseases because the creative drug design of small functional compounds is timely and requisite for various human diseases. Medical scientists know that the advent of Aspirin as an active ingredient of acetylsalicylic acid enhanced human health and welfare since the twentieth century. As acetylsalicylic acid is also a small leader compound, CA should be classified into that category. That is the reason why a naturally occurring CA is useful for drug design by scaffold structural variation and chemobiological fusion. CA should be used as a medium and substrate for the creation and development of new chemotherapeutic agents for many human diseases, several of which are fundamentally based on different origins. One should note that the naturally occurring CA derivative, CAPE, is relatively more active against specific inhibition to signaling pathways, such as intracellular phosphorylation and transcription, than the original CA. To date, the chemical syntheses of ester and amide derivatives has progressed. The present-day studies on CA and CAPE have thus, been analyzed for a future direction in their application to health fields. At present, a comprehensive series of schololarly monographs, which describes CA and related derivatives, are needed for drug design and pharmaceutical application. The purpose of this chapter is to provide a comprehensive review, based on recent reports, on the structural basis and pharmacological activities of CA and its natural derivatives. This chapter, "Molecular, pharmacological and chemical biology of Caffeic acid and derivatives," is composed of two topics: [1] General and biochemical basis of CA; and [2] Biological and pharmacological functions in the health sciences.