Synthesis of mangiferin derivatives, complexes, and carriers as potential therapeutic candidates for cancer treatment: an update

Abstract

Mangiferin (MF), a xanthonoid polyphenol, its derivatives, coordination and inclusion complexes, and carriers have demonstrated notable antitumor activity in vitro and in vivo. However, their clinical application remains limited due to MF's poor water solubility and low systemic bioavailability. This review critically summarizes advances in the synthesis of MF derivatives and formulation strategies, such as metal complexes, cyclodextrin inclusion systems, and nanocarriers, developed over the past decade to enhance MF's bioavailability and therapeutic efficacy. Promising results include glycosylated derivatives, MF-Se (IV) metal complexes, and β-cyclodextrin complexes, each contributing to improved solubility and cytotoxicity profiles. Continued research is essential to bridge the gap between experimental success and its clinical implementation in cancer therapy.

Keywords: antitumor effect; bioavailability; mangiferin; mangiferin carriers; mangiferin complexes; mangiferin derivatives.

FIGURE 1

Chemical structure of mangiferin (MF). Arrows indicate possible reaction sites, depending on the synthetic pathway to produce MF derivatives and/or complexes.

FIGURE 2

Chemical derivatives to enhance the mangiferin (MF) antidiabetic activity by inhibiting the Protein Tyrosine Phosphatase 1B (PTP1B). Reaction conditions: DMF as solvent; K₂CO₃, RX, stirring 10 h, 60°C. Derivatives 6 and 9 showed 100% and 62.5% higher inhibition than MF against PTP1B (Turkar et al., 2024).

FIGURE 3

Chemical derivatives to enhance the mangiferin (MF) antidiabetic activity in a streptozotocin-induced hyperglycemia mouse model. Reaction conditions: alkyloxy anhydride, H₂SO₄, stirring 18 h, 40°C. All derivatives showed significantly higher antidiabetic activity than MF (Turkar et al., 2024).

FIGURE 4

Chemical derivatives to enhance the mangiferin (MF) analgesic activity by inhibiting the cyclooxygenase enzyme. Reaction conditions: DMF as solvent, K₂CO₃, stirring overnight, room temperature. MF and all its derivatives had similar analgesic and anti-inflammatory effects (Turkar et al., 2024).

FIGURE 5

Chemical derivatives to enhance the antioxidant activity of mangiferin (MF) by DPPH test and inhibition of lipid peroxidation. Reaction conditions: Acetylation and cinnamoylation (alkyloxy and pyridine as solvent); Methylation (acetone, DMS, K₂CO₃, stirring between 7 and 36 h, room temperature. Derivatives 3 and 4 had higher antioxidant activity than MF by 77.2%, and 83.7%, respectively (Turkar et al., 2024).

FIGURE 6

Chemical derivatives to enhance the antitumor activity of mangiferin (MF) in breast cancer cell line (MDA-MB-231). Derivatives 6, 11, and 12 showed significantly higher cytotoxic effects than MF in this cell line (Patil et al., 2022).

FIGURE 7

Mangiferin derivatives found in aqueous mango stem bark extract by HPLC/MS-MS (Núñez-Sellés et al., 2020).

FIGURE 8

Structures of the most common cyclodextrins (CyDs) to enhance the bioavailability of poorly water-soluble bioactives. 1. α-cyclodextrin; 2. β-cyclodextrin; and 3. γ-cyclodextrin (Sharma and Baldi, 2016). (A) 2D structures; (B) 3D toroidal structure of CyDs.

FIGURE 9

Proposed structure of the mangiferin (MF)-metal complex -Cu (II) and Zn (II)- with improved inhibition of cell proliferation in cancer cell lines as compared to MF (MTT assay) (Qin et al., 2016).

FIGURE 10

Diagram of main challenges for improving mangiferin solubility and bioavailability for cancer treatment. (QSAR: Quantitative Structure-Activity Relationships, NLCs: Nanolipid Carriers, AuNPs: Gold Nanoparticles).