MEDICINAL CHEMISTRY STUDIES ON DIANHYDROHEXITOLS AS SCAFFOLDS FOR NOVEL ANTI-INFLAMMATORY DRUG DESIGN

Abstract

This thesis focuses on the design, synthesis, and evaluation of novel anti‐inflammatory compounds using dianhydrohexitol scaffolds. The primary aim was to develop more potent alternatives to the lead compound, ST0702, for the treatment of inflammatory and malignant T‐cell disorders. A soft drug approach was employed to create compounds that could provide effective localized action while being rapidly metabolised into inactive and non‐toxic byproducts, thereby minimising side effects. The lead compound, ST0702, an isosorbide‐based nicotinate, showed promising results in inhibiting T‐cell proliferation and tumour cell‐induced platelet aggregation while also demonstrating anti‐inflammatory properties in a mouse model of psoriasis. In cell‐free assays, ST0702 was found to interact weakly with Hsp90 at its C‐terminus, blocking cyclophilin binding, but showed no influence on N‐terminal binding of geldanamycin. While early antiproliferative studies were promising, issues with compound purity were identified, and further analysis revealed the presence of an impurity, underscoring the limitations of cell‐based assays in providing reliable results. In cell‐free assays, Hsp90 inhibition could not be confirmed, and the mechanism of action remained unclear. The focus then shifted toward investigating OXPHOS and the electron transport chain ETC as alternative mechanisms of action, as these compounds influenced the OCR and ECAR, indicators of mitochondrial function and cellular metabolism. SAR analysis revealed that compounds with specific features, such as a 4‐hydroxy benzoate group at the C‐2 position and nicotinate groups at the C‐5 position, were the most effective ETC inhibitors and also exhibited anti‐inflammatory properties. These compounds were found to inhibit the NF‐ κB pathway, a key driver of inflammation. The future direction of this study will focus on understanding the precise mechanism by which the ETC is inhibited and how this contributes to the reduction of inflammation, as well as exploring the therapeutic potential of these compounds in various disease models.