Advancements in Cyclodextrin Complexes with Bioactive Secondary Metabolites and Their Pharmaceutical Applications

Abstract

Cyclodextrins (CDs) have largely been investigated during the last decades for their outstanding properties, such as biocompatibility and biodegradability, with wide applications in the pharmaceutical field, among which the formation of inclusion complexes (ICs) with natural or synthetic lipophilic compounds. This review prioritizes the research of recent years (2022-2025), being focused on (1) systematization of the research of ICs based on the structure of the secondary metabolite, namely (i) polyphenols (PPs), (ii) terpenes and terpenoids (TTs), and (iii) alkaloids (Alks); (2) for each type of inclusion complex, the following aspects have been discussed: benefits of complexation, composite materials, and in vitro/in vivo and theoretical studies; and (3) pharmacokinetics and pharmacodynamics, risks, limitations, and perspectives of cyclodextrin inclusion complexes with secondary metabolites.

Keywords: alkaloids; cyclodextrins; natural compounds; polyphenols; secondary metabolites; terpenes and terpenoids.

Figure 1

Trends in the number of articles indexed in the WOS Core Collection over the last two decades. Note that the data were obtained by searching for articles with the following keywords: blue bars—“cyclodextrin” and “alkaloid”; green bars—“cyclodextrin”, “terpene” + “cyclodextrin”, and “terpenoid”; red bars—“cyclodextrin” and “polyphenol” (collection date: 10 January 2025). The vertical bars represent the number of articles indexed in the WOS Core Collection for each of the keywords detailed above and reflect the dynamics of research on each type of inclusion complex discussed in this review.

Figure 2

Representations of CDs: (a) chemical structure of α-, β-, and δ-CDs; the number of structural units (α-D-glucopyranoside) is six (for α-CD), seven (for β-CD), or eight (for δ-CDs); (b) chemical structure of α-D-glucopyranoside unit; primary (C6-OH; blue color) and secondary (C2-OH and C3-OH; violet color) hydroxyl groups are indicated; numbers 1–6 indicate C1–C6 atoms of α-D-glucopyranoside unit; (c) schematic representation of the three-dimensional shape of α-,β-, and δ-CDs, highlighting the hydrophobic and hydrophilic properties of β-CD; meaning of d, D and H notations.

Figure 3

Schematic representation of IC formation between CD and SM (a virtual general structure is represented for SM). The three types of secondary metabolites that will be reviewed in this paper are polyphenols, terpenes and terpenoids, and alkaloids. The obtained inclusion complexes offer various advantages compared to the free secondary metabolites, enabling the exploration of various pharmaceutical applications, as detailed in this paper.

Scheme 1

The molecular structures and classification of some polyphenols discussed in this review: flavonoids, phenolic acids, lignans, stilbenes, tannins, and curcuminoids.

Scheme 2

The molecular structures and classification of some terpenes and terpenoids discussed in this review.

Scheme 3

The molecular structures and classification of some alkaloids discussed in this review.