Boron-containing phenoxyacetanilide derivatives as hypoxia-inducible factor (HIF)-1a inhibitors Kazuki Shimizu, Minako Maruyama, Yuka Yasui, Hidemitsu Minegishi, Hyun Seung Ban, Hiroyuki Nakamura * Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan article info Article history: Received 31 October 2009 Revised 7 December 2009 Accepted 9 December 2009 Available online 6 January 2010 Keywords: Hypoxia inducible factor (HIF)-1a Inhibitor Carborane Boronic acid Angiogenesis HeLa cells abstract A series of boron-containing phenoxyacetanilide derivatives 8a–f, 9a–f, 15, and 16 were synthesized as hypoxia-inducible factor (HIF)-1a inhibitors. Among the compounds synthesized, carboranylphenoxy- acetanilide 16 (GN26361) was found to be a potent inhibitor against HIF-1a accumulation under hypoxic conditions and inhibited the hypoxia-induced HIF-1 transcriptional activity in HeLa cells (IC 50 = 0.74 lM). Compound 16 suppressed hypoxia-induced HIF-1a accumulation and vascular endothelial growth factor mRNA expression in a concentration-dependent manner without affecting the expression of HIF-1a mRNA. Ó 2009 Elsevier Ltd. All rights reserved. The formation of new blood vessels sprouting from existing host capillaries (angiogenesis), is a necessary process for tumors to grow beyond a certain critical size. 1,2 Specific inhibition of this tumor-induced angiogenesis prevents growth of many types of so- lid tumors and provides a novel approach for cancer treatment. Angiogenesis factors such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) are key growth factors in tumor angiogenesis. 3 Various approaches have been studied for inhibition of their signal transduction to prevent angiogenesis and suppress tumor growth. 4,5 Hypoxia-inducible factors (HIF) are heterodimeric (a/b) tran- scriptional factors and major physiological stimuli for expression of angiogenesis factors. 6–8 The levels of HIF-1a are low under normal oxygen conditions (normoxia) but increase in response to hypoxia. HIF-1b, also known as the arylhydrocarbon nuclear trans- locator, 9 is a constitutively expressed nuclear protein. Under nor- moxia, HIF-1a protein undergoes hydroxylation at specific prolyl residues by prolyl hydroxylase (PHD). This modification is recog- nized by the von Hippel–Lindau tumor suppressor protein for rapid degradation by the ubiquitin–proteasome system. 10 Under hypox- ia, the hydroxylation by PHD is compromised and HIF-1a is suffi- ciently stabilized to form a heterodimeric complex with HIF-1b. This complex binds to the hypoxia response element (HRE) DNA sequence with co-activators to activate various genes, including VEGF and EPO. 6 HIF-1a has been found in a wide variety of human primary tumors compared with corresponding normal tissue. 11–16 HIF-1 is considered to be a potential target for antineoplastic ther- apy. 17,18 Various HIF-1 inhibitors that block HIF-1 activation under hypoxic conditions have been reported ( Fig. 1). Topotecan 19 and PX-478 20,21 are undergoing phase I/II clinical trials on patients expressing high levels of HIF-1a in their tumors. 22 YC-1, originally developed as a potential therapeutic agent for circulation disor- ders, is in the lead-optimization stage. 23 Recently, AC1-001 was developed by Lee and co-workers, 24 and its benzimidazole analog (AC-004) has been reported to exhibit antitumor activity in vivo. 25 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.12.037 * Corresponding author. E-mail address: hiroyuki.nakamura@gakushuin.ac.jp (H. Nakamura). N N O OH N N O HO NMe 2 O O Me HCl OH O NH 2 N Cl Cl - O + N H OH CO 2 H O O topotecan PX-478 AC1-001 YC-1 H N H N N H O GN6767 MeO 2 C Figure 1. Structure of HIF-1 inhibitors. Bioorganic & Medicinal Chemistry Letters 20 (2010) 1453–1456 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl