New Spisulosine Derivative promotes robust autophagic response to cancer cells

• Published in: European journal of medicinal chemistry Vol. 188; p. 112011
• Main Authors: Ganesher, Asha, Chaturvedi, Priyank, Sahai, Rohit, Meena, Sanjeev, Mitra, Kalyan, Datta, Dipak, Panda, Gautam
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2020; Elsevier
• Subjects: Autophagy; Chemistry, Medicinal; Chemotherapy; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Resistance; Science & Technology; Sphingoid; Structure-activity relationship; Resistance; Chemotherapy; Sphingoid; Autophagy; Structure-activity relationship; AMINO-ALCOHOLS; D-ERYTHRO-SPHINGANINE; METABOLIC PATHWAYS; SPHINGOLIPIDS; CERAMIDE; SPONGE; ES-285; (+)-SPISULOSINE; MARINE; CYTOTOXICITY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.112011

Therapy resistance by evasion of apoptosis is one of the hallmarks of human cancer. Therefore, restoration of cell death by non-apoptotic mechanisms is critical to successfully overcome therapy resistance in cancer. By rational drug design approach, here we try to provide evidence that subtle changes in the chemical structure of spisulosine completely switched its cytotoxic function from apoptosis to autophagy. Our most potent molecule (26b) in a series of 16 synthesized derivatives showed robust autophagic cell death in diverse cancer cells sparing normal counterpart. Compound 26b mediated lethal autophagy induction was confirmed by formation of characteristic autophagic vacuoles, LC3 puncta formation, upregulation of signature autophagy markers like Beclin and Atg family proteins. Altogether, we have detected novel autophagy inducer small molecule which can be tested further for drug discovery research. Compound 26b promotes Autophagic cell death. [Display omitted] •New Spisulosine Derivative as novel autophagy inducer.•Robust autophagic cell death in diverse cancer cells.•Sparing normal counterpart.