Boron-Based Compounds

Potential and Emerging Applications in Medicine

Evamarie Hey-Hawkins, Clara Viñas Teixidor, Evamarie Hey-Hawkins, Clara Viñas Teixidor

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781119275558
• eBook ISBN: 9781119275596
• Edition: 1
• Topic: Ciencias físicas
• Subtopic: Química industrial y técnica

Noted experts review the current status of boron-containing drugs and materials for molecular medical diagnostics

Boron-Based Compounds offers a summary of the present status and promotes the further development of new boron-containing drugs and advanced materials, mostly boron clusters, for molecular medical diagnostics. The knowledge accumulated during the past decades on the chemistry and biology of bioorganic and organometallic boron compounds laid the foundation for the emergence of a new area of study and application of boron compounds as lipophilic pharmacophores and modulators of biologically active molecules.This important text brings together in one comprehensive volume contributions from renowned experts in the field of medicinal chemistry of boron compounds.

The authors cover a range of the most relevant topics including boron compounds as modulators of the bioactivity of biomolecules, boron clusters as pharmacophores or for drug delivery, boron compounds for boron neutron capture therapy (BNCT) and for diagnostics, as well as in silico molecular modeling of boron- and carborane-containing compounds in drug design. Authoritative and accessible, Boron-Based Compounds:

• Contains contributions from a panel of internationally renowned experts in the field
• Offers a concise summary of the current status of boron-containing drugs and materials used for molecular diagnostics
• Highlights the range and capacity of boron-based compounds in medical applications
• Includes information on boron neutron capture therapy and diagnostics

Designed for academic and industrial scientists, this important resource offers the cutting-edge information needed to understand the current state of boron-containing drugs and materials for molecular medical diagnostics.

Part 1
Design of New Boron‐based Drugs

1.1
Carboranes as Hydrophobic Pharmacophores: Applications for Design of Nuclear Receptor Ligands

Yasuyuki Endo

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan

1.1.1 Roles of Hydrophobic Pharmacophores in Medicinal Drug Design

A pharmacophore is a partial structure in which important functional groups and hydrophobic structure are arranged in suitable positions for binding to a receptor [1]. Typically, hydrophilic functional groups of the pharmacophore interact with the receptor by hydrogen bonding and/or ionic bonding, and the hydrophobic structure interacts with a hydrophobic surface of the receptor. While hydrogen bonding plays a key role in specific ligand–receptor recognition, the hydrophobic interaction between receptor and drug molecule is especially important in determining the binding affinity. The difference of binding constants between a ligand having a suitable hydrophobic group and a ligand without such a group can be as large as 1000‐fold. In medicinal drug design, the hydrophobic structures are often composed of aromatic and heteroaromatic rings, which also play a role in fixing the arrangement of functional groups appropriately for binding to the receptor. On the other hand, three‐dimensional hydrophobic structures are not yet widely used in drug design, even though they could be well suited for interaction with the three‐dimensional hydrophobic binding pockets of receptors. It is noteworthy that various steroid hormones target distinct steroid hormone receptors owing to differences of functionalization of the hydrophobic steroidal skeleton. The binding of the natural ligand 17β‐estradiol to human estrogen receptor‐α (ERα) is illustrated in Figure 1.1.1 as an example. The large number of steroid hormones may be a consequence of evolutionary diversification of the functions of the steroidal skeleton. In this context, we aimed to establish a new three‐dimensional hydrophobic skeletal structure for medicinal drug design.

Figure 1.1.1 Interactions of ligand with receptor (example for 17β‐estradiol with estrogen receptor‐α).

1.1.2 Carboranes as Hydrophobic Structures for Medicinal Drug Design

In the past three decades, there has been increasing interest in globular molecules. In the 1980s, dodecahedrane, which consists of sp³ carbons, was synthesized [2]; and in the 1990s, the chemistry of fullerene C₆₀, which also consists of sp² carbons, was explored [3]. However, the former is not easy to synthesize, while the latter molecule may have limited application because of its large molecular size. On the other hand, icosahedral carboranes [4] are topologically symmetrical, globular molecules, and have been known for more than half a century. The B–B and C–B bonds of 12‐vertex carboranes are approximately 1.8 angstroms in length, and the molecular size of carboranes is somewhat larger than adamantane or the volume of a rotated benzene ring. Carboranes have a highly electron‐delocalized hydrophobic surface, and are considered to be three‐dimensional aromatic compounds [5] or inorganic benzenes. The structures of these compounds are illustrated in Figure 1.1.2. But, although the use of boron derivatives for boron neutron capture therapy (BNCT) of tumors has a long history [6], relatively little attention has yet been paid to the possible use of carboranes as components of biologically active molecules, despite their desirable hydrophobic character, spherical geometry, and convenient molecular size for use in the design and synthesis of medicinal drugs.

Figure 1.1.2 Structures of globular molecules and characteristics of carboranes.

Carboranes have three isomers, ortho‐, meta‐, and para‐carboranes (Figure 1.1.2), and their rigid and bulky cage structures hold substituents in well‐defined spatial relationships. The two carbon atoms of carboranes have relatively acidic protons, which can readily be substituted with other organic groups [7]. Substituents can also be introduced selectively at certain boron atoms, to construct structures having three or more substituents, as illustrated in Figure 1.1.3 [8]. Carbocyclic skeletons often rearrange under acidic conditions, whereas carborane cage skeletons do not rearran...

Table of contents

• Cover
• Title Page
• Table of Contents
• List of Contributors
• Preface
• Part 1: Design of New Boron‐based Drugs
• Part 2: Boron Compounds in Drug Delivery and Imaging
• Part 3: Boron Compounds for Boron Neutron Capture Therapy
• Index
• End User License Agreement