Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells.

Abstract

The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC50 values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development.

• Authors: Swamy Savvemala Girimanchanaika, Dukanya Dukanya, Ananda Swamynayaka, Divya Maldepalli Govindachar, Mahendra Madegowda, Ganga Periyasamy, Kanchugarakoppal Subbegowda Rangappa, Vijay Pandey, Peter E Lobie, Basappa Basappa
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 20 (Oct 12 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34681659 (Publication Type: Journal Article)

Chemical References

• BAD protein, human
• Nitrobenzenes
• bcl-Associated Death Protein
• Serine
• 4-nitrophenethyl bromide

Topics

• Breast Neoplasms (metabolism, pathology)
• Crystallography, X-Ray
• Density Functional Theory
• Female
• Humans
• MCF-7 Cells
• Molecular Conformation
• Nitrobenzenes (chemistry, pharmacology)
• Phosphorylation (drug effects)
• Serine (metabolism)
• bcl-Associated Death Protein (metabolism)