Abstract 2801: Novel selenodiazoles as antitumor and radical scavenging agents

Abstract

Abstract Heterocyclic compounds with selenium atom in endo position, such as ebselen (EBS), have achieved very promising activity against cancer and hold an excellent pharmacological profile. In fact, EBS is currently under Phase II clinical trial for the evaluation of its therapeutic safety and efficacy. The purpose of this study was to make structural modifications over this scaffold to improve its anticancer and antioxidant characteristics. Twenty-eight novel benzo[c][1,2,5]selenodiazole-5-carboxamide derivatives were designed and synthesized. Cytotoxicity of these structures, using the MTT assay, was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). The selectivity of all the compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). For MCF-7 cells, the apoptotic status and cell cycle analysis of the cells were based on the TUNEL technique. Likewise, their radical scavenging activity was determined using the DPPH assay. Interestingly, three compounds exhibited higher cytotoxic activity than EBS in solid tumors, along with higher selectivity indexes. The cytotoxic activity of lead compound 8 was remarkable in MCF-7 cells. The antioxidant capacity of four compounds was greater than EBS. The toxicity of derivative 8 in the non-tumoral cell line 184B5 was low (lethal dose (LD50) > 100 µM) and it exhibited promising antiproliferative values in MCF-7 cells with a growth inhibition of 50% (GI50) of 3.7 µM. The radical scavenging capacity of four compounds was greater than EBS. Given the low toxicity and moderate antioxidant activity, these compounds can serve as an excellent scaffolds to achieve new and potent antioxidant compounds useful for several diseases such as cancer, neurodegenerative and heart diseases. Citation Format: Ana Carolina Ruberte, Daniel Plano, Ignacio Encio, Arun K. Sharma, Carmen Sanmartin. Novel selenodiazoles as antitumor and radical scavenging agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2801.