Design, synthesis, and biological evaluation of selective estrogen receptor modulator/histone deacetylase inhibitor hybrid drug molecules

The prognosis for those diagnosed with breast cancer has dramatically improved since the 1980’s, primarily due to improved diagnostic and treatment methods. One such treatment is a class of drugs called selective estrogen receptor modulators (SERMs). SERMs are a popular treatment option for breast cancer, commonly employed as adjuvant therapy. Prototypical examples of SERMs are tamoxifen and raloxifene. Despite their widespread success, breast cancers can often develop resistance to SERMs. As a result, other biological targets which may mitigate this resistance have been identified. Recent interest in the field has arisen around histone deacetylases (HDACs), which are a class of enzymes that have been implicated in promoting resistance in breast carcinoma. Studies have demonstrated the combination treatment of SERMs and HDAC inhibitors (HDACi’s) elicits a cooperative effect in enhancing cytotoxicity and resensitizing resistant breast cancers. In an effort to maximize the cooperative effects of SERMs and HDACi’s, the project detailed in this thesis describes the design, synthesis, and biological evaluation of a series of hybrid raloxifene/HDACi molecules that combine the pharmacophores of both drug classes. Previous work by the Gleason laboratory found tamoxifen/HDACi hybrids to exhibit potent biological activity, but further exploration of these would be laborious due to their inherent instability. As a result, a synthesis of raloxifene/HDACi hybrids was developed. Significant synthetic challenges resulted from the comparatively electron-deficient nature of key intermediates, making known methods used for raloxifene inapplicable towards these targets. After notable route scouting and reaction optimization, these challenges were resolved and a small library of seven hybrid drug molecules were successfully synthesized and purified prior to biological evaluation. Fluorogenic HDACi assays determined the IC50 values of the raloxifene/HDACi hybrids against HDAC1 and HDAC6. All hybrids demonstrated sub-micromolar IC50 values for HDAC1. For HDAC6, one hybrid showed low micromolar potency for HDAC6, while all others had sub-micromolar values. Generally, carbon-linked hybrids were more potent than oxygen-linked hybrids against HDAC1, while the reverse was true for HDAC6.Preliminary biological assays performed by the Mader lab at the Université de Montréal demonstrate all hybrids antagonize the ER at a low micromolar dose, both in the presence and in the absence of E2. A more conclusive result of the SERM/HDACi hybrids can be drawn once further biological testing has been completed by the Mader lab

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.