Synthesis and In Vitro Antitumor Activity of Naringenin Oxime and Oxime Ether Derivatives.

Ahmed Dhahir Latif,Máté Vágvölgyi,Attila Hunyadi,Tímea Gonda,István Zupkó,Ágnes Kulmány,Zoltán Péter Zomborszki,Imre Ocsovszki,Norbert Kúsz

doi:10.3390/ijms20092184

Ahmed Dhahir Latif, Máté Vágvölgyi + Show 7 more

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https://doi.org/10.3390/ijms20092184

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Abstract

Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. Tert-butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity.

Highlights

Naringenin (1) is one of the most abundant dietary flavonoids predominantly found in citrus fruits and grapes
Several in vitro studies showed that naringenin can inhibit cell proliferation and migration, and that it can induce cell cycle arrest and apoptosis in cancer cell lines, including human leukemia, hepatocellular carcinoma, colon, bladder, uterine and breast cancer [4,5,6,7,8,9,10,11]
When a ketone is converted into a corresponding oxime derivative, signals of the carbonyl carbon and both adjacent α-carbons shift upfield, and the extent of these changes show a consistent pattern since the α-syn carbons are always more shielded than the α-anti carbons [24]

Summary

Introduction

Naringenin (1) is one of the most abundant dietary flavonoids predominantly found in citrus fruits and grapes This compound exerts several beneficial pharmacological activities including antioxidant, antiviral, anti-inflammatory, anticarcinogenic and cardioprotective effects [1,2,3]. Several in vitro studies showed that naringenin can inhibit cell proliferation and migration, and that it can induce cell cycle arrest and apoptosis in cancer cell lines, including human leukemia, hepatocellular carcinoma, colon, bladder, uterine and breast cancer [4,5,6,7,8,9,10,11]. Esterification and alkylation of the 7-OH group with bulky substituents yielded compounds with improved anticancer effect against human colon cancer cells [12] Such semi-synthetic modifications afforded derivatives with significant anti-atherogenic effect in high-cholesterol fed rabbits [13]. Synthetic thiosemicarbazone derivatives were found to exert antioxidative effects and demonstrated significant DNA binding properties [15]

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