Design and Synthesis of Acridine Derivatives as Telomerase Inhibitors for the Treatment of Lung Cancer

Abstract

The current study was initiated with a thorough assessment of the cancer literature by which lung cancer has been identified as one of the deadliest cancers, among all types of cancer. It has been observed that 80-90% of malignant tumours, including lung cancer, utilize telomerase activity for achieving immortality. Numerous anti-telomerase approaches were intended for anti-cancer activity till date. However, none of the approaches has been successful in getting the FDA approval, either due to lower potency, lower selectivity or toxicity constraints. The present research emphasizes on finding novel anti-cancer agents for targeting telomerase enzyme that can provide a broad-spectrum activity with a significant reduction of toxicity. During the designing process, the biologically active scaffold was identified through pharmacophore modelling with the aid of DISCOtech refined by the GASP module in Sybyl X. Resultant of the study gave nine feature pharmacophore unit, consisted of one hydrophobic feature, one acceptor atom, one donor atom, three donor site and three acceptor sites of the receptor protein. Further, the model was validated by ROC curve and GH score analysis followed by virtual screening through the NCI database. Virtual screening helped to enrich active molecules from the randomly selected molecules. Bio-isosteric replacement was sought to replacement of functional groups or scaffolds for acquiring novel and better intellectual properties of the parent compound. newlineSimultaneously 3D-QSAR (CoMFA and CoMSIA) provided a guideline regarding the favourable and unfavourable fields of the compound responsible for telomerase inhibition. Based upon these knowledge-based approaches, hundreds of thiadiazole bearing acridine derivatives were designed and docked with telomerase protein (5CQG) which gave the idea about the essential molecular interactions with the receptor protein. In-silico ADMET explained the designed acridine-thiadiazole compounds were non-toxic and showed drug-likeness properties.