Design, Synthesis, and Molecular Docking Studies of Curcumin Hybrid Conjugates as Potential Therapeutics for Breast Cancer

Siva S. Panda, Queen L. Tran, Pragya Rajpurohit, Girinath G. Pillai, Sean J. Thomas, Allison E. Bridges, Jason E. Capito, Muthusamy Thangaraju, Bal L. Lokeshwar

Research output: Contribution to journalArticlepeer-review

Abstract

Curcumin (CUR) has received great attention over the past two decades due to its anti-cancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs.

Original languageEnglish (US)
Article number451
JournalPharmaceuticals
Volume15
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • DCA
  • amino acid
  • breast cancer
  • curcumin
  • molecular docking
  • molecular hybridization

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Design, Synthesis, and Molecular Docking Studies of Curcumin Hybrid Conjugates as Potential Therapeutics for Breast Cancer'. Together they form a unique fingerprint.

Cite this