Design and Synthesis of Novel Porcupine Inhibitors as Anticancer Agents

Abstract

Porcupine is a component of wnt signaling pathway which controls cell growth and major target used for treatment of colorectal cancer. Colorectal cancer is third prominent cause of cancer mortality, which reported over 1.2 million new patients and 600,000 deaths every year. The Wnt pathway has been appeared to be deregulated in an assortment of growths. Porcupine is a membrane bound O-acyltrasferase group of protein which catalyzes the palmitoylation of wnt proteins, required step in the rocessing of Wnt ligand secretion. For the advancement of novelty in porcupine inhibition computational approach was used. The pharmacophore model was enerated. Pharmacophore model was proposed on the basis of literature assessment. 11 assorted porcupine inhibitors generate model by Discotech module of Sybyl X with good superimposition of the pharmacophore elements. The pharmacophore model was effectively generated with 3 features consisting of one hydrophobic, one donor atom, and one acceptor atom. Pharmacophore model was validated by two different methods; via GH- score and ROC curve (0.7612, 0.9) method. Moreover, this model was screened over NCI database which presented 9291 virtual hits. These studies can be used to design and develop novel porcupine inhibitors with the help of rational drug design concept which used for the treatment of wnt driven cancer. The quinoxaline ring which is bioisostere of Isoquinoline and tetra-hydroquinolone ring, retrived as hit in virtual screening, was selected as a core moiety. Designed quinoxaline derivatives were mapped with pharmacophore model and In-Silico ADMET properties were predicted. Synthesis of highest value containing 8 quinoxaline derivatives was carried out and spectral characterization was carried out using Mass, 1H and 13C-NMR spectroscopy. Synthesized compounds were selected to In-vitro cytotoxicity studies. From the result, it was found that compound 6e displayed most potent activity.