(472) Lead Optimization of Tetrahydropyridines as Potential Breast Cancer Agents

Objective : While successful strides have been made towards developing antiestrogens for estrogen receptor positive (ER+) breast cancer (ie., tamoxifen), they are limited by adverse effects and acquired resistance. To address this gap, previously, we reported the synthesis of a novel group of compounds, known as tetrahydropyridines (THPs) where their pharmacological activity depends on the position and nature of the substituent on the THP ring structure. Preliminary studies demonstrated that THP derivatives exhibited antiproliferative activity in Ishikawa, MCF-7, and MDA-MB-231 cells. Here, the overall objective is to use lead optimization, synthesis, and biological evaluation of a series of novel THP derivatives in hormone-dependent and tamoxifen-resistant breast cancer cells. We hypothesized that novel N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridine will have lower IC50 values and higher ER binding affinities compared to the lead compound N-[4-Iodobenzylamino]-5-ethyl-1,2,3,6-tetrahydropyridine (EH4) thus improving the biological activity.

Methods: To calculate the molecular properties, drug-likeness and predict the bioactivity score, Molinspiration Cheminformatics was utilized. The synthetic scheme of the THP derivatives is: 3-Ethylpyridine reacted with O-mesitylenesulfonylhydroxylamine (O-MSH) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of the N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides yielded stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnished the target compounds, N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines. Molecular modeling studies were performed using SYBYL-X 2.1 to mimic the behavior of the THPs docked to the active site of the estrogen receptor alpha (ERα).

Results: The THP derivatives were synthesized, purified, and characterized. Biological evaluation studies using ER+ and endocrine resistant cells lines are currently underway.

Conclusions: Based on the preliminary characterization results, it is predicted that the novel derivatives will have improved biological activity compared to the parent compound.