1-[4-(2-Dimethylaminoethoxy)phenylcarbonyl]-3,5-Bis(3,4,5-Trimethoxybenzylidene)- 4-Piperidone Hydrochloride and Related Compounds: Potent Cytotoxins Demonstrate Greater Toxicity to Neoplasms than Non- Malignant Cells

Abstract

Background: The incidence of cancer has been increasing worldwide. Unfortunately, the drugs used in cancer chemotherapy are toxic to both neoplasms and normal tissues, while many available medications have low potencies. Conjugated α,β-unsaturated ketones differ structurally from contemporary anticancer medications , some of which have noteworthy antineoplastic properties.

Objectives: This study aimed to design and synthesize highly potent cytotoxins with far greater toxicity to neoplasms than to non-malignant cells.

Methods: A series of N-acyl-3,5-bis(benzylidene)-4-piperidone hydrochlorides 4a-n were prepared and evaluated against Ca9-22, HSC-2, HSC-3, and HSC-4 squamous cell carcinomas as well as against HGF, HPLF, and HPC non-malignant cells. QSAR and western blot analyses were performed.

Results: The majority of compounds display submicromolar CC₅₀ values towards the neoplasms; the figures for some of the compounds are below 10^-7 M. In general, 4a-n have much lower CC₅₀ values than those of melphalan, 5-fluorouracil, and methotrexate, while some compounds are equitoxic with doxorubicin. The compounds are far less toxic to the non-malignant cells, giving rise to substantial selectivity index (SI) figures. A QSAR study revealed that both potency and the SI data were controlled to a large extent by the electronic properties of the substituents in the arylidene aryl rings. Two representative compounds, 4f and 4g, caused apoptosis in HSC-2 cells.

Conclusion: The compounds in series 4 are potent cytotoxins displaying tumor-selective toxicity. In particular, 4g with an average CC₅₀ value of 0.04 μM towards four malignant cell lines and a selectivity index of 46.3 is clearly a lead molecule that should be further evaluated.

Keywords: Cytotoxins; apoptosis; bioassays; neoplasms; organic syntheses; selective toxicity; structure-activity relationships.