Facile synthesis of autophagonizer and evaluation of its activity to induce autophagic cell death in apoptosis-defective cell line. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Nguyen, Jennifer; Chen, Luxi; Kumar, Dhiraj; Lee, Jiyong
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4753
• Page End: 4756
• Publication Date: 2016-10-01
• Subjects: BCMZCPIZJPKEIR-UHFFFAOYSA-N; Autophagonizer -- Autophagic cell death -- Apoptosis-defective cells -- Anticancer therapeutics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.035
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A facile synthetic route is described for a novel inducer of autophagy, autophagonizer (DK-1-49). Intrinsic apoptosis is not involved with autophagonizer (DK-1-49)-induced cell death. Autophagonizer (DK-1-49) induces autophagic cell death of apoptosis-defective cells. Abstract: Some cancer cells are resistant to apoptosis, rendering them irresponsive towards apoptosis-inducing chemotherapy drugs. Another mode of action to kill these apoptosis-defective cells is essential and autophagy, a dynamic process that degrades cytoplasmic contents for cellular maintenance, has been considered as one of the alternate routes. A small molecule inducer of autophagy, autophagonizer was reported to induce cell death through a novel process that is independent of extrinsic apoptosis and the normal signaling pathways of autophagy. Here, we describe an efficient synthetic procedure for the autophagonizer. The newly synthesized autophagonizer (DK-1-49) resulted in an accumulation of autophagy-associated LC3-II and enhanced levels of autophagosomes and acidic vacuoles. Furthermore, cell viability was inhibited by autophagic cell death in not only human cancer cells but also Bax/Bak double-knockout cells. These findings highlight that intrinsic apoptosis is not also involved in the induction of cellular death by the autophagonizer suggesting the autophagonizer is a promising candidate for anticancer therapeutics for cancer cells that are resistant to apoptosis-inducing chemotherapy.