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Review
. 2022 Dec 27;17(1):145.
doi: 10.1186/s13020-022-00699-0.

Dicoumarol: from chemistry to antitumor benefits

Vera L M Silva  1 , Rita Silva-Reis  1 , Alexandra Moreira-Pais  1   2   3 , Tiago Ferreira  2   4 , Paula A Oliveira  2   4   5 , Rita Ferreira  1 , Susana M Cardoso  6 , Javad Sharifi-Rad  7 , Monica Butnariu  8 , Maria Alina Costea  9 , Ioana Grozea  9
Affiliations
Review

Dicoumarol: from chemistry to antitumor benefits

Vera L M Silva et al. Chin Med. .

Abstract

Dicoumarol, a coumarin-like compound, is known for its anticoagulant properties associated with the ability to inhibit vitamin K, being prescribed as a drug for several decades. The pharmaceutical value of dicoumarol turned it into a focus of chemists' attention, aiming its synthesis and of dicoumarol derivatives, bringing to light new methodologies. In recent years, several other bioactive effects have been claimed for dicoumarol and its derivatives, including anti-inflammatory, antimicrobial, antifungal, and anticancer, although the mechanisms of action underlying them are mostly not disclosed and additional research is needed to unravel them. This review presents a state of the art on the chemistry of dicoumarols, and their potential anticancer characteristics, highlighting the mechanisms of action elucidated so far. In parallel, we draw attention to the lack of in vivo studies and clinical trials to assess the safety and efficacy as drugs for later application.

Keywords: Anticancer; Biological activity; Coumarins; Dicoumarol; Synthesis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Structures of dicoumarol 1a,b and tautomers of 4-hydroxycoumarin 2–4
Fig. 2
Fig. 2
Generic mechanism for the formation of dicoumarol by domino Knoevenagel–Michael reaction of 4-hydroxycoumarin with aldehyde derivatives
Scheme 1
Scheme 1
Synthesis of dicoumarols catalyzed by [TBA]2[W6O19]
Scheme 2
Scheme 2
Synthesis of dicoumarol derivatives in water catalyzed by PS-Zn-anthra complex
Scheme 3
Scheme 3
Synthesis of dicoumarols using silica-based heterogeneous catalysts
Scheme 4
Scheme 4
Synthesis of dicoumarols using MgO, PVP-CuO and BiVO4 nanocatalysts
Scheme 5
Scheme 5
Synthesis of dicoumarol via the one-pot condensation of 4-hydroxycoumarin with aryl glyoxals
Fig. 3
Fig. 3
Plausible mechanism for the synthesis of dicoumarols from 4-hydroxycoumarin and aryl glyoxals in the presence of iron oxide nanoparticles
Scheme 6
Scheme 6
Synthesis of dicoumarols from 4-hydroxycoumarin in presence of Fe3O4@SiO2-SP-DMG-Ni(II) nanoparticles in water at reflux
Scheme 7
Scheme 7
Synthesis of dicoumarol catalyzed by TrBr or [Fe3O4@SiO2@(CH2)3-Im-SO3H]Cl
Scheme 8
Scheme 8
Synthesis of dicoumarol derivatives catalyzed by l-Tyrosine loaded nanoparticles
Scheme 9
Scheme 9
Synthesis of dicoumarols in water catalyzed by lipase RMIM
Fig. 4
Fig. 4
Actions of dicoumarol that may contribute to its antitumor effects. The figure was produced using Servier Medical Art. Legend—I, II, III, IV: oxidative phosphorylation complexes I, II, III and IV, respectively; cyt c: cytochrome c; CRE: cyclic adenose monophosphate response elements; JNK: c-Jun N-terminal kinase; NADH: nicotinamide adenine dinucleotide; NF-κB: nuclear factor kappa B; NQO1: NAD(P):(quinone acceptor) oxidoreductase 1; PARP: poly (adenosine diphosphate-ribose) polymerase; PDH: pyruvate dehydrogenase; PDK1: phosphoinositide-dependent kinase-1; PI3K: phosphoinositide 3-kinase; PSG1: pregnancy specific beta-1-glycoprotein 1; ROS: reactive oxygen species; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; TGFβ1: transforming growth factor beta 1; TFGβR: transforming growth factor receptor
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