Synthesis and Biological Evaluation of Small Molecule Inhibitors of BMPR1b

• Main Author: Machicao Tello, Paulo Andre
• Format: Others
• Published: BYU ScholarsArchive 2016
• Subjects: lung adenocarcinoma; small molecule inhibitors; bone morphogenetic protein receptor 1b; Chemistry
• Online Access: https://scholarsarchive.byu.edu/etd/6021; https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=7020&context=etd

Methods for preparing an array of potential small molecule inhibitors of Bone Morphogenetic Protein Receptor 1b (BMPR1b) are described. Target molecules were prepared from two general classes: (1) N9-aryl-N6-ureidoadenines, and (2) dicarbamyl iodoacetamides. Recent data from the Peterson lab indicated that both classes might bind to BMPR1b and thus inhibit this key receptor. Docking studies performed using Sureflex Dock suggested the N9-aryl-N6-ureidoadenines would bind to the active site of BMPR1b. In addition antiproliferative activities of dicarbamyl iodoacetamides previously synthesized in the Peterson lab pointed to this moiety as an attractive target for structure activity relationship (SAR) development. Compounds were prepared in good to excellent yields and 40 derivatives were screened for antiproliferative activity. Of the N9-aryl-N6-ureidoadenine derivatives, N9-phenyl-N6-N-phenylureaadenine was most potent and exhibited selective activity against HeLa cells (IC50 = 11± 1 uM). Dicarbamyl iodoacetamide derivatives had similar activities compared to the previously reported compound (JRS-150).