Boron as a platform for new drug design

Review

Boron as a platform for new drug design Laura Ciani & Sandra Ristori† 1.

Introduction

2.

Boron nitride nanotubes

3.

Boron chromophores

4.

Boron in biocompatible

University of Florence, Department of Chemistry & CSGI, Sesto Fiorentino, Italy

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by University of Florence on 09/20/12 For personal use only.

materials 5.

Boronic acid as a targeting group in drug/gene delivery

6.

Boron neutron capture therapy

7.

Expert opinion

Introduction: Boron lies on the borderline between metals and non-metals in the periodic table. As such, it possesses peculiarities which render it suitable for a variety of applications in chemistry, technology and medicine. However, boron’s peculiarities have been exploited only partially so far. Areas covered: In this review, the authors highlight selected areas of research which have witnessed new uses of boron compounds in recent times. The examples reported illustrate how difficulties in the synthesis and physicochemical characterization of boronated molecules, encountered in past years, can be overcome with positive effects in different fields. Expert opinion: Many potentialities of boron-based systems reside in the peculiar properties of both boron atoms (the ability to replace carbon atoms, electron deficiency) and of boronated compounds (hydrophobicity, lipophilicity, versatile stereochemistry). Taken in conjunction, these properties can provide innovative drugs. The authors highlight the need to further investigate the assembly of boronated compounds, in terms of drug design, since the mechanisms required to obtain supramolecular structures may be unconventional compared with the more standard molecules used. Furthermore, the authors propose that computational methods are a valuable tool for assessing the role of multicenter, quasi-aromatic bonds and its peculiar geometries. Keywords: BN nantubes, BNCT, boronated bioactive compounds, drug delivery systems Expert Opin. Drug Discov. [Early Online]

1.

Introduction

Boron is a peculiar element in the periodic table [1]. It is the smallest of semimetals, that is, hybrid metal/non-metals with properties of both. From a chemical standpoint, boron behaves similarly to metals when forming oxides such as B2O3 or salts, such as B2(SO4)3. However, alike non-metals, boron gives acids such as H3BO3. Formally, boron atoms are trivalent, but they also possess vacant p-orbitals, which make most of borocompounds electron-deficient. Boron easily forms three-center bonds whose electronic configuration allows for peculiar chemical and physical properties of the resulting molecules. For example, boron hydrides are composed of cages and clusters, rather than chains and rings as in carbon hydrides. This, in turn, confers to boron-based drugs the possibility to interact with biological targets in novel ways with respect to carbonbased compounds. Until recently, boron was not popular among biologists and pharmacists, though in trace it is essential for the health of animals and humans. Natural boroncontaining antibiotics also exist, such as boromycin, aplasmomycins, borophycin and tartrolons. Some boronated biomolecules are supposed to act as signaling molecules with respect to cell surfaces [2]. In the past, boron-based compounds have been rarely used for biomedical purposes, with the noticeable exception boron neutron capture therapy (BNCT) [3-6].

10.1517/17460441.2012.717530 © 2012 Informa UK, Ltd. ISSN 1746-0441 All rights reserved: reproduction in whole or in part not permitted

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L. Ciani & S. Ristori

Article highlights. .

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Boron is a peculiar element between metals and non-metals in the periodic table. This gives the possibility to replace carbon atoms in many structures leading to an electron deficiency. Boron nitrides are a viable alternative to carbon nanotubes (CNTs) with interesting biomedical and technological applications. These structures showed good biocompatibility, piezoelectrical capability and delivery properties that highlighted very promising performance. Boron in luminescent polymers has interesting features like: facile synthesis; good stability; a wide choice of available ligands; unusual photochemical properties; tunable absorptions and emission in the visible spectral window. Boron is a promising biocompatible material for coating surgical implants, pacemakers and cardiovascular nets. Boron and boronic acids readily interact with sugars, including those in the glicocalix of cell surface and skeletal deoxyribose of DNA. These pendants linked to polyethylene glycol (PEG) are also capable to enhance transfection efficacy in gene delivery. Boron in carboranes is the active nucleus for BNCT, an anticancer alternative radiotherapy. This is the most exploited application in the field of boron biomedical use. Computational chemistry can be used as a valid tool to implement knowledge-based approaches exploiting boron versatile chemistry for biomedical applications.

This box summarizes key points contained in the article.

Limitations were mainly due to inadequate understanding of the physical properties of boronated molecules as well as to difficulties in chemical synthesis. However, this state of circumstances is rapidly changing, since both researchers and pharmaceutical companies show increasing interest in boron as an alternative to carbon in drug design and development. A number of organoboron compounds are already used as building blocks for molecules of pharmaceutical interest [7-9]. The spherical boron cluster dicarba-closo-dodecaborane (carborane) was recognized as possible pharmacophore about 35 years ago, when it was shown to interact hydrophobically with receptors [10-12]. Later on, carboranes have demonstrated a variety of biological activities in the research about enzyme inhibition, ion channels, neurological disease and antiviral agent. Moreover, the marked hydrophobic character of carboranes was proposed as a tool for facilitating transport across membranes. In particular, medicinal chemists have used carbopolycyclic scaffolds in drug design to enhance lipophilicity, which can greatly improve transport across cell membranes such as the blood--brain barrier (BBB) and central nervous system (CNS). Marked lipophilicity can also increase the affinity of a drug for the hydrophobic region of receptor binding sites, while the rigidity of a polycyclic skeleton may 2

increase the stability of a drug toward metabolic degradation. Nowadays, these valuable characteristics of carboranes have been fully assessed and are comprehensively described in recent reviews [5,13,14][15]. As an example, Figure 1 shows the design strategy followed by Fujii et al. for preparing a vitamin D receptor ligand where a carborane cage replaces a hydrocarbon moiety of comparable size [8]. To complement this existing wealth of literature, the authors propose here a contribution on selected aspects of boron involvement in biomedical applications. 2.

Boron nitride nanotubes

Boron nitride nanotubes (BNNTs) are of interest to the scientific community because of their importance in electronic applications [16]. BNNTs are structural analogs of carbon nanotubes (CNTs), in that the BN unit is iso-electronic to and can substitute for C atoms, with almost no change in atomic spacing. However, despite this similarity, CNTs and BNNTs exhibit relevant differences [17]. Although many applications of CNTs in biomedical technology have been proposed in the past few years [18], the entire range of BNNTs potentiality is yet to be fully explored yet. This incomplete knowledge can be ascribed to the high chemical stability of BNNTs [17-19][20][21], which cause their poor dispersibility in aqueous media. Such problem has been recently solved by wrapping BNNT with covalent polymeric that allows aqueous dispersion and enhance biocompatibility [22,23]. Figure 2 shows the sequence of reaction leading to BNNT functionalization with hydrophilic groups. Ciofani et al. reported on the cytocompatibility of BNNTs toward human neuroblastoma cells and demonstrated that these tubes did not decrease viability, metabolism or cellular replication. In contrast to the more controversial uptake mechanism of CNTs [24-26], these authors showed that BNNTs entered the cells via endocytosis [22]. Bai et al. evidenced piezoelectrical properties in multiwalled BNNTs showing that electrical transport can induce structural deformation [27]. This characteristic underpins the high potentiality of BNNTs as nanoscale transducers. Ciofani et al. explored the possible use of BNNTs as nanovectors to carry electrical/mechanical signals on demand within a cellular system [28]. Electrical stimuli can be conveyed to a tissue or cell culture after BNNT internalization using ultrasounds by virtue of BNNT piezoelectric behavior. This set-up can induce the same effects as a classical electric stimulation that is marked outgrowth of neuronal processes in cell cultures, but without the need for electrodes in the culture. The same concept could also be used in life science when electrical stimulation is needed, for example, for deep brain or gastric stimuli [29,30], in cardiac pacing for various cardiac arrhythmias [31] and for skeletal muscle stimuli [32]. The results of Ciofani et al. suggest that calcium influx plays a substantial role in BNNT

Expert Opin. Drug Discov. [Early Online]

Boron as a platform for new drug design

Carborane-based acyclic triols

Secosteroid Hydrophobic core

OH

OH *

* *

Necessary three hydroxyl group

Effective hydrophibic interaction

m

HO

OH HO

OH

m, n = 0, 1

n

Figure 1. Synthetic strategy followed in [8] to prepare the carborane analog of vitamin D receptor ligand. Reproduced from [8] with permission of the American Chemical Society.

H2N

H2N

O H3C

OH

OH OH

CH3 Si O H 3C O

OH

6.5% HNO3 6h

CH3

Si O O

O

OH OH

50% E1OH 12 h CH3

OH

OH

OH OH

CH3

O

O Si O

NH2

OH

OH O

CH3

O

H3C

CH3

O O

Si

O

Si


O

O

CH3

H3C

NH2

NH2

Figure 2. Scheme of the reaction devised for coating BNNT with water compatible chemical functions. Reproduced from [23] with permission of Elsevier.

stimulation, thus corroborating the hypothesis of indirect electrical stimulation due to the piezoelectric properties of BNNTs [28]. In the field of drug delivery, BNNT could be used as vector due to their superparamagnetic properties. Technologies based on magnetic nanoparticles (MNPs) are routinely applied to biological systems for diagnostics and therapeutics. An outstanding example is magnetic resonance imaging (MRI), which relies on the strong magnetic moments of MNPs to modify proton relaxation and obtain detailed imaging of tissues [33]. Similarly, magnetic fluid hyperthermia uses MNPs as heat generators to induce localized cell damage and death [34]. These techniques are based on the interaction between external magnetic fields and MNPs.

Therefore, the magnetic moment of nanoparticles should be maximized to improve performance. Targeted drug delivery with ‘smart’ nanoparticles is the next step toward delivering reduced doses of the drug in the site of the tumor only [35-37]. It is believed that magnetic behavior in BNNTs arises from the presence of small Fe particles, which have been detected by energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM) experiments and come from the production catalysts [38]. In vitro tests performed with human neuroblastoma cells show that cellular uptake of fluorescent-labeled BNNTs can be modulated by an external magnetic field. BNNTs have therefore the potential to be used as nanovectors in magnetic-driven drug targeting [36].


3



3.

Boron chromophores

In recent years, boron chromophores and luminescent boronated polymers have drawn interest, due to facile synthesis, good stability, wide choice of available ligands, tunable absorption and emission through the entire visible spectral window, as well as for other novel photophysical properties, such as two-photon absorption, room-temperature phosphorescence and dual emission [39-41]. Fraser and collaborators have used hydroxyl-functionalized difluoroboron dibenzoylmethane (BF2dbm) as initiator for lactide polymerization [42]. Poly(lactic acid) (PLA) polymers with a luminescent BF2dbm end-group show unusual photophysical properties, that is, intense delayed fluorescence, two-photon absorption and oxygen-sensitive phosphorescence at room temperature (RTP). To investigate the biological applications of these polymers, boron-functionalized polylactide nanoparticles (BNPs) have been prepared by adding the polymer solution to water [43]. These systems were successfully used to label Chinese hamster ovary (CHO) cells (Figure 3). Taking advantage of their dual-emissive and the oxygensensitive RTP properties, they were also used as oxygen sensor and imaging agent for tumor tissue [44]. To enhance the stability of BNPs in biological conditions and facilitate tumor uptake, nanoparticles were prepared by co-precipitation of polyethylene glycol-block-poly(D-lactide) (mPEG-PDLA) and (BF2dbm(I))PLLA. In these composites, (BF2dbm(I)) PLLA and PDLA blocks form the core of the particles, while PEG blocks constitute a water-soluble shell able to stabilize the dispersion [45]. Another boron-containing fluorophore is BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), which is commercially available. It is characterized by high quantum yields, large molar absorption coefficients and good photostability. BODIPY is currently used as biolabeling agent and in the construction of electronic devices [46]. 4.

Boron in biocompatible materials

Boron is used in the coating of inert biomaterials such as metals and their alloy. These biomaterials find applications in a vast range of biomedical fields, such as surgical implants (joints, limbs, total hips, knees, artificial arteries, etc.), pacemaker leads and cardiovascular nets [47]. Diamondlike carbon (DLC) coatings, or the so-called amorphous hydrogenated carbon a-C:H, have been used for titanium alloys or stainless steel implants to avoid unwanted surface interactions with blood and tissues thank to inertness, low frictional coefficient and biocompatibility [48]. DLC coatings show excellent hemocompatibility and tribological properties which are of interest in technical applications. For instance, they are able to act as solid lubricant by forming a thin layer at the interface between articulation and attached components. [49].. However, DLC coating generally possess poor adhesive properties toward biomedical metals and alloys 4

such as titanium and stainless steel [50-52]. Ahmed et al. showed that doping DLC films with boron additives increases adhesion strength in both grade 316L stainless steel and Ti--6Al--4V titanium alloy substrates [47]. This study also shows that the B-DLC films are good polymeric biomaterial coatings when deposited on stainless steel and titanium alloys with or without silicon interfacial layers. It has been established that boron plays a role in many life processes, including embryogenesis, bone growth and maintenance, immune function and psychomotor skills. Thus, the delivery of boron by the degradation of borate glass is of special interest in these fields. For example, boronated materials can improve the attitude of implants to facilitate healing or to compensate for a lack or loss of bone tissue, particularly in osteoporotic fractures, where conventional metallic reinforcements are not applicable because of bone fragility and low mineral density. In this case, the very good performance of bioactive glass (e.g., 45S5 Bioglass) is credited to the onset of spontaneous bonds with the bone tissues through the formation of a calcium phosphate (Ca--P) layer [53-55]. The degradation of this silicon-based glass was found to be time dependent, and the bulk material remained in the human body up to 1 year from implantation [56]. However, cytotoxicity of borate glass which arises from rapid release of boron has to be carefully considered. The incorporation of strontium can significantly decrease this phenomenon. Moreover, if conversion to apatite is not complete, glass degradation in vivo will not only render boron a nutritional element for bone health, but will also deliver strontium for new bone formation [57].

Boronic acid as a targeting group in drug/gene delivery

5.

Pendant boronic acids have been reported to enhance the cytosolic delivery of protein toxins [58]. In fact, the cell surface is coated with the glycocalyx, a dense layer of polysaccharides [59] and boronic acids readily form esters with the 1,2- and 1,3-diols of sugars [60], including those in the glycocalyx [61,62]. Moreover, boronated functions are compatible with human physiology [63,64]. Pendant boronic acids linked to polyethylenimine [65] and to poly(amido amine)s [66] have been shown to enhance DNA transfection, as it is sketched in Figure 4. 6.

Boron neutron capture therapy

BNCT is a tumor treatment based on the incorporation of the stable 10B isotope into cancerous cells. Subsequent irradiation with a flux of thermal neutrons yields high-energy products with mean path length in tissues of a few microns. This distance is comparable with typical cell diameters. Therefore, selective destruction of tumors can be achieved without affecting nearby healthy tissues [3-6]. An example of tumor selectivity for BNCT applied to liver metastasis is reported in Figure 5.



F

F B

O

O

O

H O

O

n


O

Fluorescence

Phosphorescence

Figure 3 Left: luminescence images of BF2dbmPLA nanoparticles suspended in water. Right: fluorescence and bright field microscopy image overlay of CHO cells incubated for 1 h with a filtered BF2dbmPLA nanoparticle suspension. Adapted from [43] with permission from the American Chemical Society.

Although mercaptoundecahydrododecaborate (BSH; Na2B12H11SH) [67,68] and L-p-boronophenylalanine (L-BPA) [69,70] are currently used in clinical treatment with fairly good outcome, different boron-containing molecules with higher BNCT potentiality have been proposed in the latest 15 years [71]. These include boronated nucleoside [72-76], amino acids and peptides [77,78], sugars [79-82], phospholipids [83], tetrapyrroles [84-90] and monoclonal antibodies (mAbs) [91,92]. Moreover, due to the high amount of 10 B required to induce tumor cell damage (20 -- 35 g/g tumor tissue), a variety of vectors have been designed to protect borocompounds from degradation and to improve boron accumulation in tumors. Examples of well-established drug carriers include liposomes [93-96], closomers [97,98] and dendrimers [99,100]. Inorganic [101-104] and polymeric nanoparticles (micelles) [105,106] have also been prepared and tested on laboratory animals with encouraging results. An important issue for the success of BNCT is that the boron concentration in surrounding normal tissues and blood is kept low to minimize radiation damages. To improve tumor selectivity and enhance active targeting boron vectors have been conjugated with ligands such as mAb [107,108][109], folate [110], epidermal growth factor [111], transferrin [112,113] and thymidine kinase, whose activity is overexpressed in several forms of cancers [114]. 7.

Expert opinion

A key finding for the use of boron in drug discovery is related to its aptitude to replace carbon in many compounds. Boron

versatile chemistry and limited toxicity provide the basis for widespread biomedical applications. In particular, the ability of boron to be acceptor of electrons modulates the chemical properties of new boron compounds, as it is evidenced in the case of BNNTs. These structures are bio- and technological devices of great potential, and are largely unexplored at present. In recent years, boronated groups have attracted increasing interest as platforms to obtain new hydrophilic drugs. Derivatized borocompounds can be obtained with a variety of functions, thus allowing different targets. Noticeable examples include vitamin D receptor ligands, mAbs and epidermal growth factor functionalized with the carborane cage. Until one or two decades ago, most of the synthetic efforts were directed to BNCT, whose primary aim was the localization of boron into malignant cells. However, this is also the goal of other boron-containing systems, such as BN nanotubes or boronated molecules with luminescent properties, as discussed in this review. Therefore, previously acquired knowledge can be, at least partially, translated to different areas of borocompounds with positive results. On the other hand, newly synthesized molecules, such as luminescent or superparamagnetic compounds can be of help in solving BNCTrelated problems, for example, imaging for boron localization. Cutting-edge boron applications rely on the study of new classes of materials both for technological and biological purposes. A case in point could be represented by the structural and physicochemical similarity between carborane and fullerene. This latter was recognized as one of the most promising systems to be used in nanomedicine since its discovery in 1985 [115].


5


H N

*

SS

O

H+ N

H N

H N 30% O

O

SS

H+ N

H N O

HN

+

H3N

Abbreviated as p(DAB-R)R


*

70%

70-200 nm polyplex

O O

NH NH

NH

OH

R=

R=

B

R=

OH

B OH

HO

Bz = benzoyl

4CPBA = 4-carbamaoylphenylboronic acid

Benzoyl groups for additional hydrophobic interactions with the cell membrane

Phenylboronic acid for cell adhesion through boronic ester formation with the glycocalix

2AMPBA = 2-aminomethylphenylboronic acid o-Aminophenylboronic acid for improved cell adhesion at reduced pH

-

NH+

N H+

O

O

N+ H

N H

N+ H NH

H N +

NH

H N

+

H3N

-

+

-

O B

-

Cell

Cell membrane

Cell

O

-

B O O

+

H3N Glycocalix

H3N

-

-

Glycocalix Cell

-

Figure 4. Role of derivatized boronic acid groups in poly(amido amine)s for gene delivery. Adapted from [66] with permission of Elsevier.

The possibility to design novel boronated structures should be fuelled by computational chemistry. Indeed, computation and modeling methods have provided excellent clues for synthetic strategies in recent years, due to more powerful computers and new calculation procedures. The first computational studies on boronated systems were performed nearly 20 years 6

ago [116,117] and, since then, rapid improvement in computer technology has allowed to obtain novel schemes for obtaining derivatized compounds [9] and multidimentional networks [118]. An example where carborane chemistry is used for conjugation with proteins, and hence for increasing the interactions between pharmaceuticals and their targets, is described in [117]. As shown




Figure 5. Left: neutron autoradiography of a lung section (60 micron thick) Right: standard histology of a contiguous lung section. The histology evidences the presence of two metastatic nodules (bottom, right) also visible in the autoradiography. Since the darker areas of neutron autoradiography are characterized by a higher track density, these images demonstrate that boron is accumulated within the nodules in higher concentration compared with normal parenchyma. (Courtesy of Dr Saverio Altieri and Dr Silva Bortolussi, University of Pavia, Italy).

above in this review, carboranes are isosteric with rotating phenyl groups, therefore, the substitution of the former with the latter functions can be carried out in biologically active systems. This may also allow to increase the stability in vivo and the bioavailability of compounds which are normally metabolized very rapidly. To conclude, it is believed that researchers have now the ability and the tools for preparing boron-containing molecules

with high potentiality as bioactive agents into a broad field of medicinal chemistry.

Declaration of interest The authors are supported by the Center for Colloids and Surface Science (CSGI) and by the MIUR (Ministero Istruzione Universita` Ricerca).


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Affiliation

Laura Ciani & Sandra Ristori† † Author for correspondence University of Florence, Department of Chemistry & CSGI, via della Lastruccia 3, 50019, Sesto Fiorentino, Italy E-mail: [email protected]

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