Emerging Sulfated Flavonoids and other Polyphenols as Drugs: Nature as an Inspiration

Abstract

Nature uses sulfation of endogenous and exogenous molecules mainly to avoid potential toxicity. The growing importance of natural sulfated molecules, as modulators of a number of physiological and pathological processes, has inspired the synthesis of non-natural sulfated scaffolds. Until the 1990s, the synthesis of sulfated small molecules was almost restricted to derivatives of flavonoids and aimed mainly at structure elucidation and plant biosynthesis studies. Currently, the synthesis of this type of compounds concerns structurally diverse scaffolds and is aimed at the development of potential drugs and/or exploitation of the biological effects of sulfated metabolites. Some important hit compounds are emerging from sulfated flavonoids and other polyphenols mainly as anticoagulant and antiviral agents. When compared with polymeric macromolecules such as heparins, sulfated small molecules could be of value in therapeutics due to their hydrophobic nature that can contribute to improve the bioavailability. This review highlights the synthetic approaches that were applied to obtain monosulfated or polysulfated phenolic small molecules and compiles the diverse biological activities already reported for this type of derivatives. Toxicity and pharmacokinetic parameters of this emerging class of derivatives will also be considered, emphasizing their value for therapeutic applications.

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

“…These small sulfated NSGMs offer many advantages including i) adequate aqueous solubility (>25 mg/mL), which is expected to help antifibrinolytic use during surgeries, ii) limited cellular and central nervous system toxicity arising from their highly charged nature, iii) reasonable chemical stability, particularly under neutral and basic conditions [45], and iv) ease of chemical synthesis [41,46,47]. Further efforts are necessary to develop these sulfated NSGMs into clinically relevant molecules.…”

“…The monomeric scaffolds included chalcones (compounds 1-10), flavonoids (11)(12)(13)(14)(15)(16) [30][31][32], sucrose octasulfate (17) [40], quinazolinones (18 and 19) [37], and tetrahydro-isoquinolines (20)(21)(22)(23)(24)(25)(26)(27) [36], whereas the dimeric scaffolds comprised flavonoid-quinazolinone heterodimers (28)(29)(30)(31)(32)(33)(34) [37], bis-quinazolinones homodimers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) [37], and bis-flavonoid homodimers (48-55). In addition to the inherent diversity of the scaffolds in this library, NSGMs also differed in the number (1 to 8) and orientation of the sulfate groups.…”

“…New NSGMs synthesized for the first time included 10 sulfated chalcones (1-10), six sulfated bis-quinazolinones homodimers (42)(43)(44)(45)(46)(47), four sulfated flavonoid-quinazolinone heterodimers (31)(32)(33)(34), and eight sulfated bis-flavonoid homodimers (48-55). The synthesis of the new NSGMs is described in detail in Supplementary Information (Schemes S1-S6).…”

Rare Ellagic Acid Sulphate Derivatives from the Rhizome of Geum rivale L.—Structure, Cytotoxicity, and Validated HPLC-PDA Assay

“…A preparative sample (300 g) of the dried and grinded plant material was exhaustively extracted with acetone-water 70:30 (v/v) at room temperature (22)(23)(24)(25) • C) by mechanical shaking (6 × 3 L × 8 h). The combined acetone-water extracts were concentrated in vacuum until complete removal of acetone and then extracted with ethyl acetate (6 × 100 mL) to remove less polar constituents.…”

“…It was also found that increased temperature (higher than 30 • C) has a negative impact on the recovery of both analytes, which is most likely connected with their proneness to undergo hydrolysis. Finally, an extraction procedure was established that consisted of three successive extraction periods (15 min) with water (1 × 20 mL + 2 × 10 mL/1000 mg dw of the plant tissue) in room temperature (22)(23)(24)(25) • C) with the aid of mechanical shaking.…”