Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
MetadataShow full item record
Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the aß-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in aß-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.
Showing items related by title, author, creator and subject.
Wang, Z.; Chen, C.; Finger, S.; Kwajah, M.; Jung, M.; Schwarz, H.; Swanson, N.; Lareu, Ricardo; Raghunath, M. (2009)Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro ...
Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction: Role in Pediatric Cystic Fibrosis Liver DiseasePozniak, K.; Pearen, M.; Pereira, T.; Kramer, C.; Kalita-De Croft, P.; Nawaratna, S.; Fernandez-Rojo, M.; Gobert, G.; Tirnitz-Parker, Nina; Olynyk, John; Shepherd, R.; Lewindon, P.; Ramm, G. (2017)Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis; however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid–induced ductular reaction ...
Housekeeping proteins: How useful are they in skeletal muscle diabetes studies and muscle hypertrophy models?Fortes, M.; Marzuca-Nassr, G.; Vitzel, K.; Da Justa Pinheiro, C.; Newsholme, Philip; Curi, R. (2016)The use of Western blot analysis is of great importance in research, and the measurement of housekeeping proteins is commonly used for loading controls. However, Ponceau S staining has been shown to be an alternative to ...