Dimeric 3,5-Bis(benzylidene)-4-piperidones: Tumor-Selective Cytotoxicity and Structure-Activity Relationships

Swagatika Das; Praveen K Roayapalley; Hiroshi Sakagami; Naoki Umemura; Dennis K J Gorecki; Mohammad Hossain; Masami Kawase; Umashankar Das; Jonathan R Dimmock

doi:10.3390/medicines11010003

Dimeric 3,5-Bis(benzylidene)-4-piperidones: Tumor-Selective Cytotoxicity and Structure-Activity Relationships

Medicines (Basel). 2024 Jan 11;11(1):3. doi: 10.3390/medicines11010003.

Authors

Swagatika Das¹, Praveen K Roayapalley¹, Hiroshi Sakagami², Naoki Umemura³, Dennis K J Gorecki¹, Mohammad Hossain⁴, Masami Kawase⁵, Umashankar Das¹, Jonathan R Dimmock¹

Affiliations

¹ Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
² Meikai University Research Institute of Odontology, Saitama 350-0283, Japan.
³ Department of Oral Biochemistry, Asahi University School of Dentistry, Gifu 501-0296, Japan.
⁴ School of Sciences, Indiana University Kokomo, Kokomo, IN 46904-9003, USA.
⁵ Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyama 790-8578, Japan.

Abstract

Background: The objective of this study is to find novel antineoplastic agents that display greater toxicity to malignant cells than to neoplasms. In addition, the mechanisms of action of representative compounds are sought. This report describes the cytotoxicity of a number of dimers of 3,5-bis(benzylidene)-4-piperidones against human malignant cells (promyelocytic leukemia HL-60 and squamous cell carcinoma HSC-2, HSC-3, and HSC-4). Methods: Tumor specificity was evaluated by the selectivity index (SI), that is the ratio of the mean CC₅₀ for human non-malignant oral cells (gingival fibroblasts, pulp cells, periodontal ligament fibroblasts) to that for malignant cells. Results: The compounds were highly toxic to human malignant cells. On the other hand, these molecules were less toxic to human non-malignant cells. In particular, a potent lead molecule, 3b, was identified. A QSAR study revealed that the placement of electron-releasing and hydrophilic substituents into the aryl rings led to increases in cytotoxic potencies. The modes of action of a lead compound discovered in this study designated 3b were the activation of caspases-3 and -7, as well as causing PARP1 cleavage and G2 arrest, followed by sub-G1 accumulation in the cell cycle. This compound also depolarized the mitochondrial membrane and generated reactive oxygen species in human colon carcinoma HCT116 cells. In conclusion, this study has revealed that, in general, the compounds described in this report are tumor-selective cytotoxins.

Keywords: QSAR; cytotoxicity; modes of action; selective toxicity; unsaturated ketones.

Grants and funding

Funding was supplied by the Canadian Institutes of Health Research and the Saskatchewan Health Research Foundation to J.R. Dimmock and U. Das, Japan Society for the Promotion of Science JSPS who awarded a grant-in-aid to H. Sakagami (principal investigator: No. 19592156; No. 16K11519; 20K09885); while The Office of the Executive Vice Chancellor for Academic Affairs, Indiana University Kokomo, USA provided funds for M. Hossain.