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 anti-carcinogenic 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 (NFκB) 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 high-affinity 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.

Keywords: cancer; chromanols; chromenols; inflammation; molecular targets.

Figure 1

(A) Chromanol (2-methyl-3,4-dihydro-2H-chromen-6-ol) and (B) chromenol (2-methyl-2H-chromen-6-ol) core structure.

Figure 2

Core structure of (A) tocopherol and (B) tocotrienol forms.

Figure 3

Core structure of (A) tocopherol and (B) tocotrienol metabolites. The substitutions R1 to R3 are given in Figure 2 (A) and (B).

Figure 4

Core structure of sargachromanol forms.

Figure 5

Core structure of amplexichromanol forms.

Figure 6

Molecular structure of δ-sargachromenol.

Figure 7

Schematic illustration of signaling targets, pathways, and molecules involved in inflammatory response and cancer progression. Pathways were chosen due to known interactions with the compounds of interest. Inflammatory signaling molecules are interleukins (IL), tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandins (PG), prostacyclin (PGI₂), tromboxanes (TX), leukotriens (LT), and lipoxins (LX). Their expression, synthesis, or release depends, among others, on the activation of NF-κB, NLR family pyrin domain containing 3 (NLRP3) inflammasome, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and lipoxygenases (LO). In addition, membrane receptors, such as cytokine or epidermal growth factor receptors regulate the activation of nuclear receptor signal transducer and activator of transcription (STAT) 3 as well as extrinsic or intrinsic pathways which trigger the activation of caspases (Casp). These mediators are therefore important factors for modulating the balance between cell proliferation and apoptosis, which is essential to prevent carcinogenesis.

Figure 8

Heatmap illustrating the effectiveness of chromanol and chromenol structures on selected targets. If not indicated otherwise, the plotted effects represent inhibitory effects of the respective compound on distinct parameters; induced parameters are marked with an arrow (↑). The color coding of the presented heat map ranges from high-affinity targets and parameters (effect with <1 µM) presented in red to low-affinity targets and parameters (effects with >1 µM to ≤100 µM) presented in dark blue. If a compound did not affect a specific factor/parameter or showed low effectiveness (>100 µM), the factor/parameter is marked in light gray. Factors and parameters lacking data are marked in white. The heat map is considered as simplified guide for orientation and does not provide a detailed summary of the topic. All concentrations are given micromole (µM). Abbreviations used are: Actv, activation; A, activity; BA, binding affinity; C, cleavage; E, expression; PF, product formation; P, production; T, translocation.