2. Academic Validation
  3. Pyrimidine-2,4-dione targets STAT3 signaling pathway to induce cytotoxicity in hepatocellular carcinoma cells

Pyrimidine-2,4-dione targets STAT3 signaling pathway to induce cytotoxicity in hepatocellular carcinoma cells

  • Bioorg Med Chem Lett. 2021 Oct 15;50:128332. doi: 10.1016/j.bmcl.2021.128332.
Ayyiliath M Sajith 1,  Kereyagalahally H Narasimhamurthy 2,  Muthu K Shanmugam 3,  Shobith Rangappa 4,  S Chandra Nayak 5,  Arunachalam Chinnathambi 6,  Tahani Awad Alahmadi 7,  Sulaiman Ali Alharbi 6,  K R Haridas 1,  E K Reddy 8,  B Savitha 9,  Chakrabhavi Dhananjaya Mohan 10,  Kanchugarakoppal S Rangappa 11
Affiliations

Affiliations

  • 1 School of Chemical Sciences, Kannur University, Payyanur Campus, Edat P.O., Kannur 670327, India.
  • 2 Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
  • 3 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
  • 4 Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri, BG Nagara 571448, Nagamangala Taluk, India.
  • 5 Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India.
  • 6 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
  • 7 Department of Pediatrics, College of Medicine, King Saud University, [Medical City], King Khalid University Hospital, PO Box-2925, Riyadh 11461, Saudi Arabia.
  • 8 Department of Chemistry, Vignan's Foundation for Science and Technology and Research, Vadlamudi, Guntur 522213, India.
  • 9 Postgraduate and Research Department of Chemistry, Jamal Mohamed College, Bharathidasan University, Tiruchirappalli 620020, India.
  • 10 Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: [email protected].
  • 11 Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: [email protected].
PMID: 34418571 DOI: 10.1016/j.bmcl.2021.128332
Abstract

Signal transducer and activator of transcription 3 (STAT3) is a tumorigenic transcription factor that is persistently activated in various human cancers including hepatocellular carcinoma (HCC). Therefore, STAT3 is considered as a prominent target to counteract the uncontrolled proliferation of Cancer cells. In the present report, pyrimidine-2,4-diones (N-methyluracil derivatives) (MNK1-MNK14) were synthesized in an ionic liquid (BMIm PF6) medium employing a ligand-free Suzuki-Miyaura cross-coupling process. Among the 14 derivatives, compound MNK8 showed good cytotoxicity towards both the tested cell lines and did not display a toxic effect against normal hepatocytes (LO2). MNK8 significantly increased the Sub-G1 cell count in both cell lines and the cytotoxic effect of MNK8 was found to be mediated through the suppression of constitutive phosphorylation of STAT3Y705. It also decreased the DNA interaction ability of nuclear STAT3 in HCC cells. MNK8 downregulated the levels of apoptosis-related proteins (such as Bcl-2, cyclin D1, Survivin) and increased cleaved Caspase-3 inferring the apoptogenic effect of MNK8. It also reduced the CXCL12-triggered cell migration and invasion in in vitro assay systems. Overall, MNK8 has been demonstrated as a new inhibitor of STAT3 signaling cascade in HCC cells.

Keywords

Anticancer; Antimigratory agent; N-methyluracil derivatives; STAT3 inhibitor.

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