Synthesis, docking and biological activities of novel hybrids celecoxib and anthraquinone analogs as potent cytotoxic agents.

Maha Almutairi,Gehan Hegazy,Mogedda Haiba,Nagy Khalifa,Hamed Ali,Abd Soliman

doi:10.3390/ijms151222580

Abstract

Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src).

Highlights

Cancer is one of the most widespread serious diseases
Compounds 2a was obtained according to the reported method [19] while compounds 2b, c were obtained by fusion of celecoxib 1 and 2-chloropropanoyl chloride, or chlorobutyryl chloride
The docking results of the natively embedded ligands of PTKs were reasonably well comparable and well correlated to their biological methods [25,26]; these results indicated that flexible docking involving AutoDock 4.2 under our experimental parameters seems to be accurate, with small Root Mean Square Deviation (RMSD)

Summary

Introduction

Cancer is one of the most widespread serious diseases. It is characterized by uncontrolled growth of abnormal cells. The growth and metastasis of cancer cells are dependent on angiogenesis; affecting angiogenesis will be of great importance in inhibition of tumor growth, invasion, and metastasis [1]. Prostaglandins are inflammatory mediators which are highly expressed in cancer angiogenesis. Prostaglandins are derived from arachidonic acid by either Cox-1 or Cox-2 [2,3,4]. Cox-2 modulates cell proliferation and the apoptosis process, which plays an important role in cancer progression both in human and animal models malignancies [5]. A further study showed that knock-out of the Cox-2 gene could inhibit tumorgenesis [7]

Methods

Results

Conclusion