Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2010 Feb 1;20(3):912-7.
doi: 10.1016/j.bmcl.2009.12.076. Epub 2009 Dec 24.

3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy

Umashankar Das  1 , Hiroshi Sakagami, Qing Chu, Qintao Wang, Masami Kawase, Ponniah Selvakumar, Rajendra K Sharma, Jonathan R Dimmock
Affiliations
Comparative Study

3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy

Umashankar Das et al. Bioorg Med Chem Lett. .

Abstract

A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2-5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structures of the compounds in series 1–6.
Figure 2
Figure 2
The average selectivity index (SI) figures of the compounds in series 2–5 (as the hydrochloride salts) are presented along with the average CC50 values in parentheses. The R1 and R2 substituents refer to the groups indicated in Figure 1.
Figure 3
Figure 3
Percentage growth inhibition of a panel of human cancer cell lines by 5 μM of 5a.
Figure 4
Figure 4
Evaluation of 5a on the induction of internucleosomal DNA fragmentation in HL-60 and HSC-2 cells after 7 h of incubation. M is the molecular weight marker of DNA and the figures are the concentrations of 5a in μM. UV refers to ultraviolet radiation (6 J/m2/min) applied for 1 min followed by incubation of the cells for 3 h.
Figure 5
Figure 5
Effect of 5a on the induction of caspase-3 after 6 h incubation of HL-60 and HSC-2 cells. UV refers to the radiation used which is indicated in Figure 4.
Figure 6
Figure 6
Effect of 5a on the formation of acidic organelles in HSC-2 cells after 6 h incubation. HBSS refers to Hank’s balanced salt solution in which the cells were cultured for 1 h.
Figure 7
Figure 7
Cell cycle analysis of 5 μM of 5a on HT29 cells.
See this image and copyright information in PMC

References

    1. Mutus B, Wagner JD, Talpas CJ, Dimmock JR, Phillips OA, Reid RS. Anal Biochem. 1989;177:237. - PubMed
    1. Dimmock JR, Raghavan SK, Logan BM, Bigam GE. Eur J Med Chem. 1983;18:248.
    1. Chen EX, Moore MJ. In: Principles of Medical Pharmacology. 7. Kalant H, Grant DM, Mitchell J, editors. Saunders Elsevier; Toronto: 2007. p. 778.
    1. Das U, Sharma RK, Dimmock JR. Curr Med Chem. 2009;16:2001. - PMC - PubMed
    1. Chen G, Waxman DJ. Biochem Pharmacol. 1994;47:1079. - PubMed

Publication types

Grants and funding