Synthesis and Properties of α-Mangostin and Vadimezan Conjugates with Glucoheptoamidated and Biotinylated 3rd Generation Poly(amidoamine) Dendrimer, and Conjugation Effect on Their Anticancer and Anti-Nematode Activities.

Joanna Markowicz,Wojciech Rode,Łukasz Uram,Stanisław Wołowiec

doi:10.3390/pharmaceutics14030606

Joanna Markowicz, Wojciech Rode + Show 2 more

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https://doi.org/10.3390/pharmaceutics14030606

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Abstract

α-Mangostin and vadimezan are widely studied potential anticancer agents. Their biological activities may be improved by covalent bonding by amide or ester bonds with the third generation poly(amidoamine) (PAMAM) dendrimer, substituted with α-D-glucoheptono-1,4-lactone and biotin. Thus, conjugates of either ester- (G3gh4B5V) or amide-linked (G32B12gh5V) vadimezan, and equivalents of α-mangostin (G3gh2B5M and G32B12gh5M, respectively), were synthesized, characterized and tested in vitro against cancer cells: U-118 MG glioma, SCC-15 squamous carcinoma, and BJ normal human fibroblasts growth, as well as against C. elegans development. α-Mangostin cytotoxicity, stronger than that of Vadimezan, was increased (by 2.5–9-fold) by conjugation with the PAMAM dendrimer (with the amide-linking being slightly more effective), and the strongest effect was observed with SCC-15 cells. Similar enhancement of toxicity resulting from the drug conjugation was observed with C. elegans. Vadimezan (up to 200 µM), as well as both its dendrimer conjugates, was not toxic against both the studied cells and nematodes. It showed an antiproliferative effect against cancer cells at concentrations ≥100 µM. This effect was significantly enhanced after conjugation of the drug with the dendrimer via the amide, but not the ester bond, with G32B12gh5V inhibiting the proliferation of SCC-15 and U-118 MG cells at concentrations ≥4 and ≥12 μM, respectively, without a visible effect in normal BJ cells. Thus, the drug delivery system based on the PAMAM G3 dendrimer containing amide bonds, partially-blocked amino groups on the surface, larger particle diameter and higher zeta potential can be a useful tool to improve the biological properties of transported drug molecules.

Highlights

Ethylenediamine, methyl acrylate, D-glucoheptono-1,4-lactone (GHL), succinic anhydride (SucAnh), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), 4-dimethylaminopyridine (DMAP), biotin, dimethyl sulfoxide (DMSO) and other reagents used in chemical syntheses were provided by Merck KGaA (Darmstadt, Germany)
The PAMAM G3 dendrimer was converted by exhaustive glucoheptoamidation with
Against dmso-treated control obtained in Gehan’s are marked with asterisks * (p ≤ 0.05) in the colours corresponding to the tested concentrations

Summary

Introduction

Many natural and synthetic compounds with anticancer potential are not active enough in terms of bioavailability and full exploitation of their biological properties. Α-Mangostin (αM), the main representative of the xanthones family, exhibits anticancer activity through various molecular mechanisms, the most important of which are the induction of mitochondriamediated apoptosis and the inhibition of proliferation, migration, invasion, and angiogenesis [2–6]. These activities were confirmed with in vitro and in vivo models of brain [7], pancreatic [8], liver [9], cervical [10], prostate [11] and colorectal [12] cancers. Another xanthone, vadimezan (5,6-dimethylxanthenone-4-acetic acid, DMXAA, ASA404), is an analogue of flavone acetic acid, considered one of the most promising antivascular agents. Direct and indirect mechanisms of action have been proposed for Vadimezan (V)

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