Synthesis and Preliminary Cytotoxicity Evaluation of 3-Lup-20(29)-Ene-3β,28-Diol Glycoconjugates Containing a Succinic Linker and a 1,2,3-Triazole Ring

TL;DR

Scientists created new versions of a natural compound called betulin by attaching sugar units to improve its cancer-fighting potential and selectivity.

Contribution

A novel glycoconjugation method was developed to enhance betulin's anticancer activity and selectivity using a succinic linker and triazole ring.

Findings

Ten new betulin glycoconjugates were synthesized with good yields and purity.

The glycoconjugates showed higher cytotoxicity against breast cancer cells (MCF-7) compared to normal cells.

Abstract

3-Lup-20(29)-ene-3β,28-diol (betulin, BN) is a natural bioactive compound with broad biological activities, especially anticancer, antibacterial, anti-inflammatory, and antiretroviral. However, poor bioavailability and low intracellular accumulation limit its pharmaceutical application. A promising strategy to enhance BN’s therapeutic potential is glycoconjugation. We developed an efficient method for modifying the betulin backbone at position C28 with sugar units via a (CO)CH2CH2COOH linker, based on CuAAC, yielding ten new betulin glycoconjugates with good yields and purity confirmed by spectroscopic analysis (NMR, HRMS).

Background: 3-Lup-20(29)-ene-3β,28-diol (betulin, BN) is a natural bioactive compound with significant synthetic and pharmacological potential. A growing body of research highlights the increasing interest in BN and its derivatives, driven by their broad biological activities (anticancer, antibacterial, anti-inflammatory, antiretroviral). However, poor bioavailability and low intracellular accumulation limit its pharmaceutical application. Methods: A promising strategy to enhance BN’s therapeutic potential is glycoconjugation. This approach improves drug bioavailability, solubility, and selectivity, particularly in cancer therapy, by leveraging cancer cells’ heightened glucose demand and overexpression of glucose transporters. Incorporating an N-heterocyclic linker, such as a 1,2,3-triazole ring, further enhances biological activity. Results: We developed an efficient method for modifying the betulin backbone at position C28 with sugar units via a (CO)CH2CH2COOH linker, based on CuAAC, yielding ten new betulin glycoconjugates with good yields and purity confirmed by spectroscopic analysis (NMR, HRMS). The potential for inhibition of cancer cell proliferation (HCT-116 human colorectal carcinoma cell line and MCF-7 human breast cancer cell line) and cytotoxicity toward normal human dermal fibroblasts (NHDF-Neo) was assessed. Conclusions: The obtained glycoconjugates exhibited higher activity against MCF-7, indicating the selectivity of their action. The development of glycoconjugates based on increased glucose demand and overexpression of its transporters could be an interesting strategy for acquiring anticancer agents, combining innovative chemical solutions with biological complexity. Such an approach may be crucial in the effective fight against cancer diseases.

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