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. 2021 Nov 25;26(23):7132.
doi: 10.3390/molecules26237132.

Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts

Praveen K Roayapalley  1 , Jonathan R Dimmock  1 , Lisett Contreras  2 , Karol S Balderrama  2 , Renato J Aguilera  2 , Hiroshi Sakagami  3 , Shigeru Amano  3 , Rajendra K Sharma  4 , Umashankar Das  1
Affiliations

Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts

Praveen K Roayapalley et al. Molecules. .

Abstract

A novel series of 1-[3-{3,5-bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone oximes 3a-h and related quaternary ammonium salts 4a-h were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series 3 and 4 to be potent cytotoxins with submicromolar CC50 values in virtually all cases. In contrast, the compounds were less cytocidal towards HGF, HPLF and HPC non-malignant cells revealing their tumour-selective toxicity. Quantitative structure-activity relationships revealed that, in general, both cytotoxic potency and selectivity index figures increased as the magnitude of the Hammett sigma values rose. In addition, 3a-h are cytotoxic towards a number of leukemic and colon cancer cells. 4b,c lowered the mitochondrial membrane potential in CEM cells, and 4d induced transient G2/M accumulation in Ca9-22 cells. Five compounds, namely 3c,d and 4c-e, were identified as lead molecules that have drug-like properties.

Keywords: QSAR; conjugated unsaturated ketones; cytotoxins; mitochondrial membrane potential; oximes; quaternary ammonium salts.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Design of the compounds in series 4.
Scheme 1
Scheme 1
Synthetic chemical route for the compounds in series 3 and 4.
Figure 2
Figure 2
Dose–response curves of the cytotoxicity of three representative compounds. Human oral squamous cell carcinoma cell lines (Ca9-22, HSC-2, HSC-4) and human normal oral cells (HGF, HPLF, HPC) were incubated for 48 h without (control) or with the indicated concentrations of 3d (A), 4c (B) and 4d (C), and the relative viable cell number was determined. Each value represents the mean ± S.D. of triplicate assays.
Figure 3
Figure 3
Comparison of the antitumor activity expressed as SI (A) and PSE (B) between series 3 (3a–h) and 4 (4a–h). These data are derived from Table 1 and Table 2.
Figure 4
Figure 4
4d induced cell spreading and transient accumulation of the G2/M phase cells. Ca9-22 cells were treated for 24 h without (A), or with actinomycin D (1 μM) (B), 4d (0.02, 0.1 or 0.5 μM) (C–E). (Upper column) Morphological changes. (Lower column) Cell cycle analysis.
Figure 5
Figure 5
Effect of 4b and 4c on the mitochondrial membrane potential of CEM cells. The concentrations of 4b and 4c are the CC50 or twice the CC50 values. The asterisks above the bar graphs indicate that the p-value is less than 0.05 compared to dimethylsulfoxide.
See this image and copyright information in PMC

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