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Review
. 2023 Nov 24;28(23):7763.
doi: 10.3390/molecules28237763.

Progress in Antimelanoma Research of Natural Triterpenoids and Their Derivatives: Mechanisms of Action, Bioavailability Enhancement and Structure Modifications

Marta Grudzińska  1   2   3 , Bogna Stachnik  1 , Agnieszka Galanty  1 , Agnieszka Sołtys  1 , Irma Podolak  1
Affiliations
Review

Progress in Antimelanoma Research of Natural Triterpenoids and Their Derivatives: Mechanisms of Action, Bioavailability Enhancement and Structure Modifications

Marta Grudzińska et al. Molecules. .

Abstract

Melanoma is one of the most dangerous forms of skin cancer, characterized by early metastasis and rapid development. In search for effective treatment options, much attention is given to triterpenoids of plant origin, which are considered promising drug candidates due to their well described anticancer properties and relatively low toxicity. This paper comprehensively summarizes the antimelanoma potential of natural triterpenoids, that are also used as scaffolds for the development of more effective derivatives. These include betulin, betulinic acid, ursolic acid, maslinic acid, oleanolic acid, celastrol and lupeol. Some lesser-known triterpenoids that deserve attention in this context are 22β-hydroxytingenone, cucurbitacins, geoditin A and ganoderic acids. Recently described mechanisms of action are presented, together with the results of preclinical in vitro and in vivo studies, as well as the use of drug delivery systems and pharmaceutical technologies to improve the bioavailability of triterpenoids. This paper also reviews the most promising structural modifications, based on structure-activity observations. In conclusion, triterpenoids of plant origin and some of their semi-synthetic derivatives exert significant cytotoxic, antiproliferative and chemopreventive effects that can be beneficial for melanoma treatment. Recent data indicate that their poor solubility in water, and thus low bioavailability, can be overcome by complexing with cyclodextrins, or the use of nanoparticles and ethosomes, thus making these compounds promising antimelanoma drug candidates for further development.

Keywords: antimelanoma activity; delivery systems; structural modifications; triterpenoids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Graphical summary of the strategies to improve bioavailability and antimelanoma effect of triterpenoids.
Figure 2
Figure 2
Backbone structures of betulin, betulinic acid, lupeol and their derivatives.
Figure 3
Figure 3
Chemical structure of 30-phosphate derivatives of betulin: 30-Diethoxyphosphoryloxy-28-propynoylbetulin (A) and 28-(2-butynoyl)-30-diethoxyphosphoryloxybetulin (B).
Figure 4
Figure 4
Chemical structure of acetyl-30-(1H-1,2,4-triazole-3-ylsulfanyl)-betulinic acid (BA-TZ).
Figure 5
Figure 5
Chemical structure of 3β-oleate-20S-hydroxydammar-24-en (A), 3β-oleate-20S,24S-epoxy-25-hydroxydammarane (B), 20S-hydroxydammar-24-en-3-on (C), 3β,20S-dihydroxy-dammar-24-en (D) and 20S,24S-epoxy-3β,25-dihydroxydammarane (E).
Figure 6
Figure 6
Chemical structure of 4-isoquinolinyl amide of 3-O-acetyl-betulinic acid.
Figure 7
Figure 7
Chemical structure of glycyrrhetinic acid (A) and its derivative 3-O-prenyl glycyrrhetinic acid (NPC-402) (B).
Figure 8
Figure 8
Backbone structure of oleanolic acid and its derivatives.
Figure 9
Figure 9
Chemical structure of (A) CDDO (2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid) and (B) CDDO-Me (2-cyano-3,12-dioxo- oleana-1,9(11)-dien-28-acid methyl ester).
Figure 10
Figure 10
Backbone structure of maslinic acid and its derivatives.
Figure 11
Figure 11
Chemical structure of EM2.
Figure 12
Figure 12
Backbone structure of celastrol and its derivatives.
Figure 13
Figure 13
Backbone structure of ursolic acid and its derivatives.
Figure 14
Figure 14
Chemical structures of benzotriazole esters of BA: 1H-Benzotriazole-1-yl (3β) 3-hydroxy-20(29)-lupaene-28-oate (A), OA: 1H-Benzotriazole-1-yl (3β) 3-hydroxyolean-12-en-28-oate (B) and UA: 1H-Benzotriazole-1-yl (3β) 3-hydroxyurs-12-en-28-oate (C).
Figure 15
Figure 15
Graphical summary of the antimelanoma potential of natural triterpenoids.
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