Design Synthesis and Biological Evaluation of Novel Anticancer Heterocyclic Molecules as Wnt Signaling Inhibitors

Abstract

Cancer is the second leading cause of death globally as per the WHO and its burden is newlineincreasing due to lack of physical activity, tobacco usage and unhealthy diet. Wnt signaling newlinepathway plays a key role in normal cell growth, differentiation and migration. Aberrant newlineactivation results into uncontrolled cell growth which is a hallmark of cancer. Different newlinecomponents of wnt signaling pathway like porcupine, frizzled receptor, and#946;-catenin, axin, newlinetankyrase etc. are druggable targets to target Wnt signaling pathway. Porcupine enzyme plays newlinea crucial role in the first step of Wnt signaling and activates the pathway. We aimed to develop newlinenovel Wnt/porcupine inhibitors as anticancer agents. To design novel heterocyclic porcupine newlineinhibitors, homology model of porcupine enzyme was built using two independent software newlinetools; I-TASSER and ICM-Molsoft Pro. Generated homology models were compared and the newlinebest model was run for MD simulation, binding site identification and molecular docking of newlineknown porcupine inhibitors. Key amino acid interactions were identified. Based on scaffold newlinehopping approach of existing known and potent porcupine inhibitors, two sets of novel newlineheterocyclic molecule series I and II were designed, docked and evaluated for their ADMET newlineproperty prediction. Compounds were further evaluated for structural novelty by individual newlineand markush structure search using sci-finder database. Total 41 novel compounds in two newlinedifferent series were synthesized, characterized in detail using IR, Mass, 1H and 13C NMR newlinespectroscopy. %Purity was determined for each molecule using HPLC analysis. newlineThermodynamic aqueous solubility of the promising compound from each series was also newlinedetermined using HPLC, Solubility of the lead compounds, VGBP-S1-13 and VGBP-S2-06 newlinewas found to be 64.5 and#956;g/ml and 106.5 and#956;g/ml respectively. All the synthesized compounds were newlinefirst evaluated in-vitro for their Wnt inhibitory activity in relative Topflash gene reporter assay. newlineThe best compound of series I compound 55l and 55n (VGBP-S1-13 and 15) showed IC50 o