sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine

We describe herein for the first time our medicinal electronomics bricolage design of hypoxiatargeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxiatargeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxiatargeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas. Most current cancer therapies target tumor cells directly. Recently, a newly emerging area of cancer or neoplastic therapeutics focuses instead on targeting cells of the tumorspecific environment or microenvironment (1). The hypoxic tumor environment is now considered a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. For three decades, we have been concentrating much effort on the development of chemical modifiers of cancer treatment (2), including hypoxic cell radiosensitizers, hypoxic cytotoxins, hypoxia-targeting antineoplastic drugs (3), and Gc protein-derived macrophage-activating factors (4, 5). We provide here a thorough review of our strategy and tactics for drug design as a medicinal electronomics bricolage. In particular, we review our current progress in the development of hypoxia-targeting drugs, such as antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore elucidation. We also present here our development of an in vivo developing chick embryo model to evaluate the radiosensitizing activity of compounds against solid neoplasms. We also describe our design and syntheses of new compounds that target hypoxic-neoplastic cells by functioning as indoleamine 2.3-dioxygenase (IDO) inhibitors. We further show that our hypoxia-targeting boron neutron capture therapy (BNCT) agents are promising boron-10 carrier candidates for BNCT. Finally, we present here our concept of what we call ‘boron tracedrugs’ as a new drug class with broad potential and also as next-generation pharmaceutical drugs. Boron tracedrugs are designed to have persistent traceability anytime during their lifetime. The key structural feature of these drugs consists of having multiple boron atoms firmly embedded in their scaffold or skeleton located at a position that will have little or no influence on other functional group moiety or pharmacophores. 3233 Correspondence to: Hitoshi Hori, Department of Life System, Institute of Technology and Science, Graduate School, the University of Tokushima, Minamijosanjimacho-2, Tokushima 7708506, Japan. Tel: +81 886567514, Fax: +81 886569164, e-mail: [email protected]