Research Article: Synthesis of magnolol and honokiol derivatives and their effect against hepatocarcinoma cells

Date Published: February 7, 2018

Publisher: Public Library of Science

Author(s): Margherita Maioli, Valentina Basoli, Paola Carta, Davide Fabbri, Maria Antonietta Dettori, Sara Cruciani, Pier Andrea Serra, Giovanna Delogu, Andrea Motta.

http://doi.org/10.1371/journal.pone.0192178

Abstract

The hepatocellular carcinoma is one of the most common malignant tumour with high level of mortality rate due to its rapid progression and high resistance to conventional chemotherapies. Thus, the search for novel therapeutic leads is of global interest. Herein, a small set of derivatives of magnolol 1 and honokiol 2, the main components of Magnolia grandiflora and Magnolia obovata, were evaluated in in vitro assay using tumoral hepatocytes. The pro-drug approach was applied as versatile strategy to the improve bioactivity of the compounds by careful transformation of the hydroxyl groups of magnolol 1 and honokiol 2 in suitable ester derivatives. Compounds 10 and 11 resulted to be more potent than the parental honokiol 2 at concentration down to 1 μM with complete viability of treated fibroblast cells up to concentrations of 80 μM. The combination of a butyrate ester and a bare phenol-OH group in the honokiol structure seemed to play a significant role in the antiproliferative activity identifying an interesting pharmacological clue against hepatocellular carcinoma.

Partial Text

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide with an estimated incidence of half a million new cases per year around the world [1, 2]. HCC is a frequent complication of liver cirrhosis. Major risk factors for the development of HCC are obesity, diabetes mellitus, non-alcoholic fatty liver disease, excessive alcohol consumption and dietary aflatoxin B1 [3]. Nowadays, there is no definitive curative treatment for HCC; moreover, treatment and management modalities exist with differing advantages and disadvantages [4]. Hence, novel therapeutics are urgently needed for the treatment of HCC patients.

Recent evidences suggest an important role of antioxidants and anti-inflammatory drugs in fighting liver diseases [51]. In different situation, antioxidants may exert either beneficial or detrimental effects on reactive oxygen species (ROS) homeostasis [52]. Within this context magnolol 1 and honokiol 2, the bioactive phytochemicals contained in Magnolia officinalis, are uncommon antioxidants bearing isomeric bisphenol cores. Antioxidant properties of both biphenyls have been recently studied, highlighting the role of intramolecular and intermolecular interactions and excluding the generation of superoxide radical by reaction with molecular oxygen [18, 53]. Involvement of allyl groups in the antioxidant activity of magnolol 1 and honokiol 2 has been also excluded [53]. Nevertheless, the presence of hydroxylated substituents in magnolol derivatives can affect the antioxidant activity of the resulting compound [18]. Recently, magnolol 1 and honokiol 2 have been used in combination with chemotherapies, improving the activity of the drug [32, 35]. For these reasons, the structure of magnolol 1 and honokiol 2 at the phenolic OH-group was manipulated by ester derivatives using an acetyl or a butyryl group. Ten derivatives of magnolol 1 and honokiol 2 were synthesized (Fig 1) and compared with their parental natural compounds for the ability of inhibiting the proliferation of tumoural hepatic cells (HepG2) and human foreskin fibroblasts (HFF1). Although magnolol 1 and honokiol 2 are regioisomers, the different position of one phenol-OH group conferred them distinct conformations and, thus, diverse reactivity. Phenol-OH groups in magnolol 1 have different acidity due to the formation of an intramolecular H-bond between the two phenol-OH groups that stabilises the mono anion formed in presence of one equivalent of base [53]. Thus, a delayed deprotonation of the second phenol-OH, in the presence of one equivalent of base, allowed us to better control the formation of monosubstituted esters, obtainable in high yield. Moreover, a C2-symmetry axis in magnolol 1 allowed for only one monoester isomer. On the contrary, in honokiol 2, the large dihedral angle and the distance of the two phenol-OH groups reduced the conjugation effect. Moreover similar reactivity towards a base was observed, although, a different acidity was highlighted in a range of pH between 8.6 and 9.8, where the deprotonation is mainly due to the phenol-OH in 2-position [54]. At higher pH, the two phenol-OH group in honokiol 2 were both deprotonated, thus, under strong basic conditions, steric effects might influence the reactivity of phenol-OH group favouring the 4ʹ position, as observed in monoprotection of honokiol 2 with acylic group (e.g. compounds 6 and 12).

A small set of derivatives of magnolol 1 and honokiol 2, efficiently prepared under sustainable conditions, in the range between 1–80 μM, affected tumoural hepatocytes cells proliferation while fibrablast cells, used as control for the toxicological effect of the drugs, were unaffected. The pro-drug approach was applied as versatile strategy to improve bioactivity of compounds by careful transformation of the hydroxyl groups of magnolol 1 and honokiol 2 in a suitable ester derivative. The combination of a butyrate ester and a bare phenol-OH group in the honokiol structure played a significant role in the antiproliferative activity and identified an interesting pharmacological lead against hepatocellular carcinoma. Further studies are already being performed in hepato-tumoural cells to identify the molecular effect of these honokiol and magnolol derivatives during cell cycle (G1, G2 and S check points) and apoptosis.

 

Source:

http://doi.org/10.1371/journal.pone.0192178

 

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