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

Ayyiliath M Sajith; Kereyagalahally H Narasimhamurthy; Muthu K Shanmugam; Shobith Rangappa; S Chandra Nayak; Arunachalam Chinnathambi; Tahani Awad Alahmadi; Sulaiman Ali Alharbi; K R Haridas; E K Reddy; B Savitha; Chakrabhavi Dhananjaya Mohan; Kanchugarakoppal S Rangappa

doi:10.1016/j.bmcl.2021.128332

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. Epub 2021 Aug 19.

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: cd.mohan@yahoo.com.
¹¹ Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: rangappaks@gmail.com.

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 STAT3^Y705. 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Carcinoma, Hepatocellular / drug therapy*
Cell Line, Tumor
Cell Survival / drug effects
Down-Regulation
Gene Expression Regulation, Neoplastic / drug effects
Humans
Liver Neoplasms / drug therapy*
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction

Substances

Antineoplastic Agents
STAT3 Transcription Factor
STAT3 protein, human