Design, synthesis and biological evaluation of a new thieno[2,3-d]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines.

Abstract

Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-d]pyrimidine based urea derivative, KM6. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. KM6 retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, KM6 reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, KM6 is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms.

• Authors: Marwa Sharaky, Marwa Kamel, Marwa A Aziz, Mervat Omran, Monira M Rageh, Khaled A M Abouzid, Samia A Shouman
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 35 Issue 1 Pg. 1641-1656 (Dec 2020) ISSN: 1475-6374 [Electronic] England
• PMID: 32781854 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Pyrimidines
• thieno(2,3-d)pyrimidine
• Tamoxifen
• Urea

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tamoxifen (pharmacology)
• Urea (analogs & derivatives, chemistry, pharmacology)