Synthesis and Cytotoxic Activity of Madecassic Acid-Silybin Conjugate Compounds in Liver Cancer Cells

04 March 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Madecassic acid – isolated from the medicinal herb Centella asiatica – and its derivatives exhibit cytotoxic activity against the HepG2 liver cancer cell line. Silybin, a natural compound from Silybum marianum, is well-known as a hepatoprotective agent. This paper describes the synthesis of madecassic acid-silybin conjugate compounds and evaluation of their cytotoxic activity against a range of liver cancer cell lines. Depending on the reaction conditions, the direct conjugation products of 2,3,23-triacetylmadecassic acid and silybin were found to be either an ester at position 7 of silybin (40%) and its 2,3-dehydrated derivative (20%), a 2,3-dehydrated ester at position 3 of silybin (42%), or an ester at position 3 of silybin with madecassic acid. We have also used linkers such as glycine, β-alanine and 11-aminoundecanoic acid. For further diversification, 2,3,23-triacetylmadecassic acid was dehydrated to form the Δ5,6-compound, and was converted to amide derivatives on reaction with glycine or β-alanine, and finally condensed with silybin to afford esters at position 3 of silybin. In total, sixteen new conjugates have been synthesized. The conjugates were tested in vitro for their cytotoxic effect on HepG2 cells using the MTT assay. Results confirmed the conjugated compounds demonstrated a stronger cytotoxic effect versus those of the parent compounds. Of these compounds, the most promising conjugate, compound 8, was evaluated for cytotoxic activity on the Hep3B, Huh7, and Huh7R liver cancer cell lines and also for induction of apoptosis. This compound caused a rapid and significant induction of caspase 3 activity in HepG2 cells and induced cell cycle arrest in S phase, effects distinct from the activity of madecassic acid. This is the first study on the synthesis and the cytotoxicity of the madecassic acid-silybin conjugates, and of their testing against liver cancer cell lines and provides evidence for a distinct biological profile versus madecassic acid alone.

Keywords

Madecassic acid
Silybin
Drug conjugates
Liver cancer

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