The inhibitory potency of isoxazole‑curcumin analogue for the management of breast cancer: A comparative in vitro and molecular modeling investigation

Rodrigues, Fiona C and Anilkumar, N V and Gangadhar, Hari and Pai, KSR and Thakur, Goutam (2021) The inhibitory potency of isoxazole‑curcumin analogue for the management of breast cancer: A comparative in vitro and molecular modeling investigation. Chemical Papers, 75. pp. 5995-6008. ISSN 0366-6352

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Curcumin, a potent phytochemical derived from the spice element turmeric, has been identifed as a herbal remedy decades ago and has displayed promise in the feld of medicinal chemistry. However, multiple traits associated with curcumin, such as poor bioavailability and instability, limit its efectiveness to be accepted as a lead drug-like entity. Diferent reactive sites in its chemical structure have been identifed to incorporate modifcations as attempts to improving its efcacy. The diketo group present in the center of the structural scafold 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 cur�cumin 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 efcacy, 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 profled for their ADME properties as well as free energy binding calculations. Further, the in vitro cytotoxic evalu�ation 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 signifcant cancer proteins and hence deserves further investigations in the development of small molecule-based anti-breast cancer agents.

Item Type: Article
Uncontrolled Keywords: Curcumin · Heterocyclic · Analogues · Molecular docking · Breast cancer
Subjects: Engineering > MIT Manipal > Biomedical
Engineering > MIT Manipal > Chemistry
Depositing User: MIT Library
Date Deposited: 07 Jan 2022 09:26
Last Modified: 07 Jan 2022 09:26

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