Thieno[3,2-d]pyrimidine derivatives 25(Korea University)

Acute liver injury (ALI) is a major pathological event in various liver diseases and remains a significant global medical challenge in terms of prevention and treatment. RIPK2, as a novel therapeutic target, has shown promise in the treatment of various inflammatory diseases, and it also holds potential for addressing acute liver injury. In this study, starting from a patent compound, computer-aided drug design and targeted structural optimization were employed to develop a new RIPK2 inhibitor with a thieno[3,2-d]pyrimidine core scaffold. Compound HY3 exhibited an IC₅₀ of 11 nM against RIPK2, with high selectivity for RIPK2 over RIPK1. HY3 demonstrated favorable pharmacokinetic properties, with a bioavailability of 46.6 %, and displayed significant anti-inflammatory and hepatoprotective effects in an APAP-induced ALI model. These promising results suggest that HY3 warrants further preclinical and clinical development as a potential treatment for ALI.

Topoisomerases are crucial enzymes that manage DNA topology and are essential for biological processes. Dysregulation of topoisomerases has been closely linked to the development and progress of cancer. As a result, topoisomerase inhibitors have emerged as potential anti-cancer drugs. In the current study fifteen hexahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed and synthesized to investigate their topoisomerase II inhibitory activity. The antiproliferative activity of all the synthesized derivatives was evaluated across a panel of 60 cancer cell lines at the National Cancer Institute. Compound 8 was further investigated at 5 dose concentrations due to its remarkable growth inhibiting activity. Furthermore, the three compounds with significant cytotoxic activity 6c, 8, and 9a, were tested in an in vitro topoisomerase IIα inhibition assay compared to etoposide as reference drug. Compound 8 displayed the highest topoisomerase II inhibitory activity with an IC₅₀ of 41.67 ± 3.89 μM compared to etoposide (IC₅₀ = 99.86 ± 5.02 μM). In addition, the cell cycle analysis proved that compound 8 induced cell growth arrest at the G2/M phase in colon HT-29 cell line. Also, compound 8 significantly increased the total apoptotic ratio by 19.1-fold. This apoptotic activity was supported by an increase in the level of caspase-3 in colon HT-29 cell line by 8.49 and 8.63-fold for 6c and 8, respectively. Molecular docking was performed for compounds 6c, 8 and 9 to estimate their binding modes at the active site of human topoisomerase IIα enzyme and correlate it with their measured biological activity. In conclusion, compound 8 represents a promising Topoisomerase II inhibitor with potent antiproliferative and apoptotic effects, demanding further investigation as a potential anticancer therapy.