Preliminary Study of Structure-Activity Relationship of Xanthone and Jacareubin Derivatives in Inhibiting Aromatase Activity via in Vitro and in-Silico Approaches  

Salsabiilaa M. Razib^1,*, Nadiah Mad Nasir^1,*, J Stanslas ², Muhammad A M. Latif ³,  Nur Qurratu Ain A. Nordin¹, Pavithren Devakrishnan¹ 

Abstract

Introduction: Jacareubin is a plant-derived natural xanthone that has a strong inhibitory effect on human breast cancer cells. According to a previous study, Jacareubin is less toxic and more effective than the conventional medication, 5-Fu (IC50 17.01±0.23), with an IC50 of 6.28±0.47. (Sun et al., 2016). Strong interactions were discovered in the binding pocket of aromatase (3EQM) by an initial molecular docking study on Jacareubin. However, there is still a dearth of knowledge regarding how this structure would affect the binding strength of these compounds. We propose that changes to the main structure of Jacareubin with a more varied array of substituents will significantly affect inhibitory activity of the xanthonoids. Methods: The Grover, Shah, and Shah (GSS) reaction is used to synthesis xanthonoids in a single pot. It involves phenol-benzoic acid condensation followed by direct cyclization of the benzophenone intermediate to produce the xanthonoid product. Nuclear Magnetic Resonance (NMR), Gas Chromatography-Mass Spectrometry (GC-MS), and Fourier Transform Infrared Spectroscopy (FTIR) are used to analyze newly synthesized compounds. The biological activity of the synthetic xanthonoids is evaluated against breast cancer cell lines via MTT assay. Results: There are nine xanthones and seven Jacareubin derivatives that have been synthesized. The molecular docking study shows that the derivatives have higher binding energy (-8.3 kcal/mol to -9.8 kcal/mol) than the Jacareubin (-9.4 kcal/mol) which the value of IC50 is 6.28±0.47μM. The IC50 value for 8-fluoro-1,3-dihydroxy-9H-xanthen-9-one (-8.3 kcal/mol) and 9-fluoro-5- hydroxy-2,2-dimethylpyrano[3,2-b] xanthen-6(2H)-one (-9.8 kcal/mol) are 3 μM and 60 μM respectively. Conclusion: The preliminary study showed that the IC50 value of 9- fluoro-5- hydroxy-2,2-dimethylpyrano[3,2-b] xanthen-6(2H)-one was higher than the Jacareubin due to how intensely this derivative interacts with aromatase binding sites (3EQM). Aromatase and ligand have a binding energy of -9.8 kcal/mol. Thus, this Jacareubin derivative may prevent human breast cancer from spreading throughout the body. 

Keywords: Xanthone, Jacareubin, Gemcitabine, Breast cancer, Aromatase. 

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