Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization libraries

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Thiazolidinone compounds exhibit selective toxicity against non-small cell lung cancer (NSCLC) cells, including drug-resistant types.
• These compounds demonstrate low toxicity towards normal human fibroblasts (NHFB).
• A significant limitation is their very low aqueous solubility (approximately 0.1 μg/ml).

Purpose of the Study:

• To enhance both the aqueous solubility and anti-cancer efficacy of thiazolidinone lead compounds.
• To design and synthesize novel thiazolidinone derivatives through lead optimization.
• To evaluate the improved compounds using high-throughput screening methods.

Main Methods:

• Design and synthesis of two lead-optimization libraries of thiazolidinone compounds.
• Systematic modifications of R(1), R(2), and R(3) substitutions.
• Simultaneous high-throughput assays for solubility and cytotoxicity.
• Consecutive library synthesis and iterative testing.

Main Results:

• Achieved a 5-fold improvement in aqueous solubility, increasing from 0.1 μg/ml to 0.5 μg/ml.
• Demonstrated a 10-fold enhancement in anti-cancer activity, with EC50 values improving from 0.72-0.98 μM to 0.08-0.16 μM.
• Identified a new lead thiazolidinone compound (compound 31) with superior properties.

Conclusions:

• Lead optimization strategies successfully improved thiazolidinone compound solubility and anti-cancer potency.
• Compound 31 represents a promising candidate for further development in non-small cell lung cancer therapy.
• The developed high-throughput screening approach is effective for accelerating drug discovery in this area.