Optimized imidazole-thieno[3,2-c]quinolines: promising antiproliferative compounds for thyroid and NCI60 cancer cells

Medullary thyroid cancer (MTC), a highly aggressive endocrine malignancy, is characterized by mutations in key oncogenic targets, including RET kinase. Targeting these signaling pathways is a promising approach to improve MTC therapeutic treatment [1]. Lead optimization studies [2], allowed us to develop a new series of thieno[3,2-c]quinolines 1a-l (Figure 1) with a hydrophilic imidazole moiety, to enhance both pharmacokinetic and pharmacodynamic profiles. The thienoquinolines were successfully prepared by appropriate multistep procedures and characterized spectroscopically. In vitro evaluation of derivatives 1a-l showed remarkable IC50 values in the 0.5-5.7 μM range against two MTC cell lines, TT(RETM918T) and MZ-CRC-1(RETC634R), which are known to be responsive to only a limited spectrum of anticancer drugs. Additionally, all the synthesized compounds were screened by the National Cancer Institute (NCI) under the Developmental Therapeutic Program (DTP) and tested on sixty human cell lines belonging to nine different cancer panels. Six derivatives were selected for further 5-dose assays and exhibited sub-micromolar IC50 values, particularly against leukemia and NSCLC panels (ranging from 0.1 to 4.9 μM). Ongoing in vitro biological testing will better clarify the mechanism of action (effects on cell cycle regulation, apoptotic pathways, and inhibition of key targets).