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Abstract
In the present study, a series of 4-acyloxy robustic acid derivatives were synthesized and characterized for evaluation of their anti-cancer activity. The structures of these derivatives were elucidated by mass spectra (MS) nuclear magnetic resonance spectra (NMR). The single-crystal X-ray diffraction structure of one of these compounds was obtained, for further validation of the target compound structures. The anticancer activities of the target products were evaluated against human leukemic cells HL-60, human non-small cell lung carcinoma cells A-549, human hepatic carcinoma cells SMMC-7721, human hepatocellular carcinoma cells HepG2, and human cervical carcinoma cells Hela. Three compounds among them exhibited potent in-vitro cytotoxicity and excellent DNA topoisomerase I inhibitory activity, even at 0.1 mM concentrations. The most noteworthy observation was the minor toxicity of two of these compounds to normal cells, with an activity similar to the positive control in cancerous cells. A Surflex-Dock docking study was performed to investigate the topoisomerase I activity of all compounds. Of all the other compounds, the most sensitive compound was selected for further investigation of its effect on apoptosis induction and cell cycle regulation in HL-60 cells. Our results suggest that the anticancer effects of these compounds can be attributed to their pharmacological effects on topoisomerase I, cell apoptosis, and cell cycle. These findings suggest that robustic acid derivatives could be used as potential antitumor drugs.
Highlights
Coumarin compounds are widely distributed in nature, especially in higher plants [1]
DNA topoisomerase I (Topo I) is an important enzyme in all living organisms, and it participates in many cellular metabolic processes, such as replication, transcription, recombination, and repair [19]
We infer that the anti-proliferative activity of 4-acyloxy derivatives of robustic acid (RA) to these three cells may be related to Topo I
Summary
Coumarin compounds are widely distributed in nature, especially in higher plants [1]. Pyranocoumarins (including linear type and angular type) are an interesting class of fused coumarins They are important as photoactive drugs with important pharmacological effects that include anti-inflammatory [3], anti-HIV-1 [4], anti-hepatitis B virus [5], anti-cancer [6], and antinociceptive properties [7]. As the major constituents from Clausena or Angelica genus plants [8,9,10,11], some linear-type pyranocoumarins (shown in Figure 1) with anti-cancer property have become compounds of growing research interest. Examples of such compounds are, clausenidin (1), nordentatin (2), clausarin (3), dInetn. Ccyotnostiodxeircinmgetchheawniisdme sapnedctsrturumctoufrbei-oalcotigvicitayl raecltaivtiiotinesshoifptshoefstehceosme lpinoeuanrd-tsy, ptheepsyyrnatnhoecsoisuomf anreiwnsliisnsetairll pliymraitneodcoinumthaerliintesrhaatus rder.aCwonnssiidgenriifincgantht eatwteindteiosnpeinctrreucmenot fybeiaorlso.gical activities of these compounds, the synthesis of new linear pyranocoumarins has drawn significant attention in recent years
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