Thienopyrimidine derivatives exert their anticancer efficacy via apoptosis induction, oxidative stress and mitotic...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Thieno[2,3d]pyrimidine derivatives are a class of heterocyclic compounds with diverse biological activities.
• Developing novel anti-cancer agents with improved efficacy and selectivity is a critical area of research.
• Understanding the mechanisms of cancer cell death is essential for designing effective therapies.

Purpose of the Study:

• To synthesize and evaluate a series of novel thieno[2,3d]pyrimidine derivatives for their cytotoxic activity against various cancer cell lines.
• To identify potent and selective anti-cancer compounds with potential therapeutic applications.
• To elucidate the mechanisms underlying the anti-cancer effects of the lead compound.

Main Methods:

• Synthesis of 13 structural variants of thieno[2,3d]pyrimidine derivatives (compounds 6a-6m).
• Cytotoxicity screening against colorectal, ovarian, and brain cancer cell lines, and a normal epithelial cell line (CHO) for selectivity assessment.
• Evaluation of compound 6j's effects on clonogenic potential, reactive oxygen species (ROS) formation, apoptosis, and mitotic catastrophe.

Main Results:

• Compound 6j demonstrated potent and selective cytotoxicity against colon (HCT116, HCT15), brain (LN-229, GBM-10), and ovarian (A2780, OV2008) cancer cell lines, with IC50 values ranging from 0.6-1.2 μM.
• Compound 6j exhibited significantly lower toxicity towards normal CHO cells (IC50 = 14 ± 1.3 μM), indicating good selectivity.
• Compound 6j inhibited clonogenic potential and induced ROS formation, apoptosis, and mitotic catastrophe in cancer cells, with apoptosis being the predominant mechanism in A2780 cells.

Conclusions:

• Compound 6j is a promising lead molecule for the development of novel anti-cancer therapeutics.
• The selective cytotoxicity of compound 6j is mediated through the induction of oxidative stress, apoptosis, and mitotic catastrophe.
• Compound 6j's ability to induce mitotic catastrophe, even in the absence of key apoptotic proteins, suggests a versatile mechanism of action against cancer cells.