Design of Carborane-Based Hypoxia-Inducible Factor Inhibitors

Abstract

Cancer is a disease involving uncontrolled cell growth. In a solid tumor, cancer cells are deprived of oxygen due to their rapid growth. As a result, the oxygen concentration of the tumor regions distant from blood vessels is significantly lower than that of healthy tissues, causing hypoxia in tumor. Tumor hypoxia upregulates a number of genes involved in tumor angiogenesis, cellular energy metabolism, metastasis, cell prolifera‐ tion, and resistance to apoptosis. Hypoxia‐inducible factor (HIF) is a transcriptional factor that plays an important role as an oxygen sensor in cells. HIF is a heterodimer composed of α subunits (HIF1α, ‐2α, and ‐3α) and a β subunit (HIF1β, which is also known as an aryl hydrocarbon receptor nuclear translocator [ARNT]) [1,2]. Under aerobic conditions, posttranslational hydroxylation of proline residues in HIF1α by prolyl hydroxylase (PHD) induces ubiquitination by the von Hippel–Lindau (VHL) tumor suppressor protein, a component of the E3 ubiquitin ligase complex, resulting in the oxygen‐dependent degradation through a ubiquitin– proteasome pathway. Under hypoxic conditions, HIF1α does not undergo the oxygen‐dependent degradation due to the inactivation of PHD; instead, it translocates into the nucleus, where it dimerizes with the constitutively expressed HIF1β to form a heterodimeric complex. HIF binds to the hypoxia response element (HRE) DNA sequence with co‐activators to activate various genes, including glucose transporters, glycolytic enzymes, angiogenic growth factors, and several molecules involved in apoptosis and cell proliferation [3,4]. The activated HIF plays pivotal roles in various pathological conditions, including inflammation, cardiovascular disorder, and cancer. Indeed, overexpression of HIF1α has been observed in human cancers, including brain, breast, colon, lung, ovary, and prostate cancers [5]; thus, HIF1α is a novel target of cancer therapy. We have studied a boron‐based medicinal drug design. A boron atom has a vacant orbital and readily interconverts between the neutral sp2 and anionic sp3 hybridization Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors Guangzhe Li, Hyun Seung Ban, and Hiroyuki Nakamura