ISSN print edition: 0366-6352
ISSN electronic edition: 1336-9075
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The inhibitory potency of isoxazole-curcumin analogue for the management of breast cancer: A comparative in vitro and molecular modeling investigation

Fiona C. Rodrigues, N. V. Anil Kumar, Gangadhar Hari, K. S. R. Pai, and Goutam Thakur

Department of Biomedical Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India

 

E-mail: goutam.thakur@manipal.edu

Received: 11 February 2021  Accepted: 4 July 2021

Abstract:

Curcumin, a potent phytochemical derived from the spice element turmeric, has been identified as a herbal remedy decades ago and has displayed promise in the field of medicinal chemistry. However, multiple traits associated with curcumin, such as poor bioavailability and instability, limit its effectiveness to be accepted as a lead drug-like entity. Different reactive sites in its chemical structure have been identified to incorporate modifications as attempts to improving its efficacy. The diketo group present in the center of the structural scaffold has been touted as the group responsible for the instability of curcumin, and substituting it with a heterocyclic ring contributes to improved stability. In this study, four heterocyclic curcumin analogues, representing some broad groups of heterocyclic curcuminoids (isoxazole-, pyrazole-, N-phenyl pyrazole- and N-amido-pyrazole-based), have been synthesized by a simple one-pot synthesis and have been characterized by FTIR, 1H-NMR, 13C-NMR, DSC and LC–MS. To predict its potential anticancer efficacy, the compounds have been analyzed by computational studies via molecular docking for their regulatory role against three key proteins, namely GSK-3β—of which abnormal regulation and expression is associated with cancer; Bcl-2—an apoptosis regulator; and PR which is a key nuclear receptor involved in breast cancer development. One of the compounds, isoxazole-curcumin, has consistently indicated a better docking score than the other tested compounds as well as curcumin. Apart from docking, the compounds have also been profiled for their ADME properties as well as free energy binding calculations. Further, the in vitro cytotoxic evaluation of the analogues was carried out by SRB assay in breast cancer cell line (MCF7), out of which isoxazole-curcumin (IC50–3.97 µM) has displayed a sevenfold superior activity than curcumin (IC50–21.89 µM). In the collation of results, it can be suggested that isoxazole-curcumin behaves as a potential lead owing to its ability to be involved in a regulatory role with multiple significant cancer proteins and hence deserves further investigations in the development of small molecule-based anti-breast cancer agents.

Graphic abstract

Keywords: Curcumin; Heterocyclic; Analogues; Molecular docking; Breast cancer

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-021-01775-9

 

Chemical Papers 75 (11) 5995–6008 (2021)

Monday, May 20, 2024

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2.146
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0.365
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