Diversity of Chromanol and Chromenol Structures and Functions: An Emerging Class of Anti-Inflammatory and Anti-Carcinogenic Agents

Abstract

Natural chromanols and chromenols comprise a family of molecules with enormous structural diversity and biological activities of pharmacological interest. A recently published systematic review described more than 230 structures that are derived from a chromanol ortpd chromenol core. For many of these compounds structure-activity relationships have been described with mostly anti-inflammatory as well as anticarcinogenic activities. To extend the knowledge on the biological activity and the therapeutic potential of these promising class of natural compounds, we here present a report on selected chromanols and chromenols based on the availability of data on signaling pathways involved in inflammation, apoptosis, cell proliferation, and carcinogenesis. The chromanol and chromenol derivatives seem to bind or to interfere with several molecular targets and pathways, including 5-lipoxygenase, nuclear receptors, and the nuclear-factor "kappa-light-chain-enhancer" of activated B-cells (NFkB) pathway. Interestingly, available data suggest that the chromanols and chromenols are promiscuitively acting molecules that inhibit enzyme activities, bind to cellular receptors, and modulate mitochondrial function as well as gene expression. It is also noteworthy that the molecular modes of actions by which the chromanols and chromenols exert their effects strongly depend on the concentrations of the compounds. Thereby, low-and highaffinity molecular targets can be classified. This review summarizes the available knowledge on the biological activity of selected chromanols and chromenols which may represent interesting lead structures for the development of therapeutic anti-inflammatory and chemopreventive approaches.

Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?

“…Within the hepatically formed metabolites of vitamin E, SCMs as metabolic end-products were first described in relation to anti-proliferative and anti-inflammatory properties in cancer and immune cells, respectively [ 215 ]. In addition, the LCM of vitamin E, which are the first hepatic products formed during the metabolism of vitamin E, are described to make valuable contributions to the biological activity of vitamin E. Long-chain metabolites and their precursors, tocopherols and tocotrienols, differ only in the terminal oxidation of the side-chain, and thus, similar modes of action can be assumed.…”

“…Birringer et al allocated the substructures of different forms and metabolites of vitamin E to specific functional moieties, assigning the LCM, with a terminal hydroxyl and carboxyl group at the side-chain, as structures with higher anti-inflammatory activity than their parent chromanols and chromenols [ 216 ]. Indeed, research on these metabolites has revealed the effects of LCM on inflammatory processes [ 217 , 218 , 219 , 220 ] and lipid metabolism [ 221 , 222 ], thus providing evidence of their physiological relevance [ 215 ]. A recent study by our group investigating the effect of δ-T3-13′-COOH on the progression of atherosclerosis showed protective effects on intra-plaque inflammation, as measured by nitrotyrosine [ 219 ].…”

Controlled Release of the α-Tocopherol-Derived Metabolite α-13′-Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing

“…Tocopherols are an effective form of vitamin E, a term that usually describes a group of lipid-soluble molecules with anti-oxidative and non-anti-oxidative properties. Tocopherols are known to be antioxidants with a proven independent anti-inflammatory effect [ 10 , 11 ]. More recently, it has been shown that vitamin E deficiency may contribute to the onset of degenerative disorders, immune pathologies, and even atherosclerosis [ 12 , 13 , 14 ].…”

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

“… 6 − 8 LCMs are produced from α-tocopherol ( 1a ) and other vitamin E forms ( 1b–d, 6a–d ) by hepatic ω-oxidation, yielding ω-alcohols and then ω-carboxylic acids, which are excreted via bile and feces, shortened by successive β-oxidations, or conjugated with sulfate or glucoronate for urinary elimination. 7 , 8 The LCMs α-T-13′-CH 2 OH ( 9a ) and α-T-13′-COOH ( 12a ) were detected at low nanomolar concentrations in human plasma, albeit with strong variation between individuals. 6 , 8 , 9 These differences in 1a metabolism may provide an explanation for the mixed outcomes of human vitamin E intervention studies 8 , 10 , 11 and open the door toward personalized pharmacotherapy.…”

“…Deficiency of vitamin E causes a dysfunctional immune response, degenerative diseases, and potentially atherosclerosis and Alzheimer’s disease. − The discovery that the vital antioxidant vitamin E mediates immune functions through endogenous long-chain metabolites (LCMs) recently revived research on this field. − LCMs are produced from α-tocopherol ( 1a ) and other vitamin E forms ( 1b–d, 6a–d ) by hepatic ω-oxidation, yielding ω-alcohols and then ω-carboxylic acids, which are excreted via bile and feces, shortened by successive β-oxidations, or conjugated with sulfate or glucoronate for urinary elimination. , The LCMs α-T-13′-CH 2 OH ( 9a ) and α-T-13′-COOH ( 12a ) were detected at low nanomolar concentrations in human plasma, albeit with strong variation between individuals. ,, These differences in 1a metabolism may provide an explanation for the mixed outcomes of human vitamin E intervention studies ,, and open the door toward personalized pharmacotherapy. Notably, LCMs reach the highest concentration in the liver, which correlates with the recently confirmed clinical efficiency of 1a in nonalcoholic fatty liver disease (NAFLD) …”