Boron as a platform for new drugdesignLaura Ciani & Sandra Ristori†
University of Florence, Department of Chemistry & CSGI, Sesto Fiorentino, Italy
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 physico-
chemical 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, lipo-
philicity, 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 stand-point, 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, whichmake most of borocompounds electron-deficient.
Boron easily forms three-center bonds whose electronic configuration allowsfor peculiar chemical and physical properties of the resulting molecules. For exam-ple, boron hydrides are composed of cages and clusters, rather than chains andrings as in carbon hydrides. This, in turn, confers to boron-based drugs the possi-bility to interact with biological targets in novel ways with respect to carbon-based compounds.
Until recently, boron was not popular among biologists and pharmacists, thoughin trace it is essential for the health of animals and humans. Natural boron-containing antibiotics also exist, such as boromycin, aplasmomycins, borophycinand tartrolons. Some boronated biomolecules are supposed to act as signalingmolecules with respect to cell surfaces [2].
In the past, boron-based compounds have been rarely used for biomedical pur-poses, with the noticeable exception boron neutron capture therapy (BNCT) [3-6].
Limitations were mainly due to inadequate understanding ofthe physical properties of boronated molecules as well as todifficulties in chemical synthesis.However, this state of circumstances is rapidly changing,
since both researchers and pharmaceutical companies showincreasing interest in boron as an alternative to carbon indrug design and development. A number of organoboroncompounds are already used as building blocks for moleculesof pharmaceutical interest [7-9].The spherical boron cluster dicarba-closo-dodecaborane
(carborane) was recognized as possible pharmacophore about35 years ago, when it was shown to interact hydrophobicallywith receptors [10-12]. Later on, carboranes have demonstrateda variety of biological activities in the research about enzymeinhibition, ion channels, neurological disease and antiviralagent. Moreover, the marked hydrophobic character ofcarboranes was proposed as a tool for facilitating transportacross membranes. In particular, medicinal chemists haveused carbopolycyclic scaffolds in drug design to enhance lipo-philicity, which can greatly improve transport across cellmembranes such as the blood--brain barrier (BBB) and centralnervous system (CNS). Marked lipophilicity can also increasethe affinity of a drug for the hydrophobic region of receptorbinding sites, while the rigidity of a polycyclic skeleton may
increase the stability of a drug toward metabolic degradation.Nowadays, these valuable characteristics of carboranes havebeen fully assessed and are comprehensively described inrecent reviews [5,13,14][15].
As an example, Figure 1 shows the design strategy followedby Fujii et al. for preparing a vitamin D receptor ligandwhere a carborane cage replaces a hydrocarbon moiety ofcomparable size [8].
To complement this existing wealth of literature, theauthors propose here a contribution on selected aspects ofboron involvement in biomedical applications.
2. Boron nitride nanotubes
Boron nitride nanotubes (BNNTs) are of interest to thescientific community because of their importance in elec-tronic applications [16]. BNNTs are structural analogs ofcarbon nanotubes (CNTs), in that the BN unit isiso-electronic to and can substitute for C atoms, with almostno change in atomic spacing. However, despite this simi-larity, CNTs and BNNTs exhibit relevant differences [17].
Although many applications of CNTs in biomedical tech-nology have been proposed in the past few years [18],the entire range of BNNTs potentiality is yet to be fullyexplored yet. This incomplete knowledge can be ascribed tothe high chemical stability of BNNTs [17-19][20][21], whichcause their poor dispersibility in aqueous media. Suchproblem has been recently solved by wrapping BNNT withcovalent polymeric that allows aqueous dispersion andenhance biocompatibility [22,23].
Figure 2 shows the sequence of reaction leading to BNNTfunctionalization with hydrophilic groups.
Ciofani et al. reported on the cytocompatibility of BNNTstoward human neuroblastoma cells and demonstrated thatthese tubes did not decrease viability, metabolism or cellularreplication. In contrast to the more controversial uptakemechanism of CNTs [24-26], these authors showed thatBNNTs entered the cells via endocytosis [22]. Bai et al.evidenced piezoelectrical properties in multiwalled BNNTsshowing that electrical transport can induce structural defor-mation [27]. This characteristic underpins the high potentialityof BNNTs as nanoscale transducers. Ciofani et al. exploredthe possible use of BNNTs as nanovectors to carry electri-cal/mechanical signals on demand within a cellular system [28].Electrical stimuli can be conveyed to a tissue or cell cultureafter BNNT internalization using ultrasounds by virtue ofBNNT piezoelectric behavior. This set-up can induce thesame effects as a classical electric stimulation that is markedoutgrowth of neuronal processes in cell cultures, but withoutthe need for electrodes in the culture. The same concept couldalso be used in life science when electrical stimulation isneeded, for example, for deep brain or gastric stimuli [29,30],in cardiac pacing for various cardiac arrhythmias [31] and forskeletal muscle stimuli [32]. The results of Ciofani et al. suggestthat calcium influx plays a substantial role in BNNT
Article highlights.
. Boron is a peculiar element between metals andnon-metals in the periodic table. This gives thepossibility to replace carbon atoms in many structuresleading to an electron deficiency.
. Boron nitrides are a viable alternative to carbonnanotubes (CNTs) with interesting biomedical andtechnological applications. These structures showedgood biocompatibility, piezoelectrical capability anddelivery properties that highlighted verypromising performance.
. Boron in luminescent polymers has interesting featureslike: facile synthesis; good stability; a wide choice ofavailable ligands; unusual photochemical properties;tunable absorptions and emission in the visiblespectral window.
. Boron is a promising biocompatible material for coatingsurgical implants, pacemakers and cardiovascular nets.
. Boron and boronic acids readily interact with sugars,including those in the glicocalix of cell surface andskeletal deoxyribose of DNA. These pendants linked topolyethylene glycol (PEG) are also capable to enhancetransfection efficacy in gene delivery.
. Boron in carboranes is the active nucleus for BNCT, ananticancer alternative radiotherapy. This is the mostexploited application in the field of boronbiomedical use.
. Computational chemistry can be used as a valid tool toimplement knowledge-based approaches exploitingboron versatile chemistry for biomedical applications.
This box summarizes key points contained in the article.
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stimulation, thus corroborating the hypothesis of indirectelectrical stimulation due to the piezoelectric properties ofBNNTs [28].
In the field of drug delivery, BNNT could be used asvector due to their superparamagnetic properties. Technolo-gies based on magnetic nanoparticles (MNPs) are routinelyapplied to biological systems for diagnostics and therapeu-tics. An outstanding example is magnetic resonance imaging(MRI), which relies on the strong magnetic moments ofMNPs to modify proton relaxation and obtain detailedimaging of tissues [33]. Similarly, magnetic fluid hyperther-mia uses MNPs as heat generators to induce localized celldamage and death [34]. These techniques are based on theinteraction between external magnetic fields and MNPs.
Therefore, the magnetic moment of nanoparticles shouldbe maximized to improve performance. Targeted drug deliv-ery with ‘smart’ nanoparticles is the next step toward deliver-ing reduced doses of the drug in the site of the tumoronly [35-37]. It is believed that magnetic behavior in BNNTsarises from the presence of small Fe particles, which havebeen detected by energy dispersive spectroscopy (EDS) andtransmission electron microscopy (TEM) experiments andcome from the production catalysts [38]. In vitro tests per-formed with human neuroblastoma cells show that cellularuptake of fluorescent-labeled BNNTs can be modulated byan external magnetic field. BNNTs have therefore the poten-tial to be used as nanovectors in magnetic-driven drugtargeting [36].
HO OH
Secosteroid
Hydrophobiccore
Necessary threehydroxyl group
OH OH
O
HO OH
m
n
Carborane-basedacyclic triols
m, n = 0, 1
Effectivehydrophibicinteraction
* *
*
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.
6.5%6 h
HNO3 50% E1OH12 h
H3C
CH3
H2N H2N
H3C
CH3
CH3
CH3
CH3
CH3
H3CH3C
NH2 NH2
NH2
CH3
O Si Si
Si Si
O
O O
O
O
O
OO
OO
O OO
O
OH
OH OH OH OH
OH OH OH OH
OH OH
OH
Si
Figure 2. Scheme of the reaction devised for coating BNNT with water compatible chemical functions.Reproduced from [23] with permission of Elsevier.
Boron as a platform for new drug design
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3. Boron chromophores
In recent years, boron chromophores and luminescent boro-nated polymers have drawn interest, due to facile synthesis,good stability, wide choice of available ligands, tunableabsorption and emission through the entire visible spectralwindow, as well as for other novel photophysical properties,such as two-photon absorption, room-temperature phospho-rescence and dual emission [39-41].Fraser and collaborators have used hydroxyl-functionalized
difluoroboron dibenzoylmethane (BF2dbm) as initiator forlactide polymerization [42]. Poly(lactic acid) (PLA) polymerswith a luminescent BF2dbm end-group show unusual photo-physical properties, that is, intense delayed fluorescence,two-photon absorption and oxygen-sensitive phosphorescenceat room temperature (RTP). To investigate the biologicalapplications of these polymers, boron-functionalized polylac-tide nanoparticles (BNPs) have been prepared by adding thepolymer solution to water [43]. These systems were successfullyused to label Chinese hamster ovary (CHO) cells (Figure 3).Taking advantage of their dual-emissive and the oxygen-sensitive RTP properties, they were also used as oxygen sensorand imaging agent for tumor tissue [44]. To enhance thestability of BNPs in biological conditions and facilitate tumoruptake, nanoparticles were prepared by co-precipitation ofpolyethylene 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, whilePEG blocks constitute a water-soluble shell able to stabilizethe dispersion [45].Another boron-containing fluorophore is BODIPY
(4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), which is com-mercially available. It is characterized by high quantum yields,large molar absorption coefficients and good photostability.BODIPY is currently used as biolabeling agent and in theconstruction of electronic devices [46].
4. Boron in biocompatible materials
Boron is used in the coating of inert biomaterials such asmetals and their alloy. These biomaterials find applicationsin a vast range of biomedical fields, such as surgical implants(joints, limbs, total hips, knees, artificial arteries, etc.), pace-maker leads and cardiovascular nets [47]. Diamond-like carbon (DLC) coatings, or the so-called amorphoushydrogenated carbon a-C:H, have been used for titaniumalloys or stainless steel implants to avoid unwanted surfaceinteractions with blood and tissues thank to inertness, lowfrictional coefficient and biocompatibility [48]. DLC coatingsshow excellent hemocompatibility and tribological propertieswhich are of interest in technical applications. For instance,they are able to act as solid lubricant by forming a thin layerat the interface between articulation and attached compo-nents. [49].. However, DLC coating generally possess pooradhesive properties toward biomedical metals and alloys
such as titanium and stainless steel [50-52]. Ahmed et al.showed that doping DLC films with boron additives increasesadhesion strength in both grade 316L stainless steel andTi--6Al--4V titanium alloy substrates [47]. This study alsoshows that the B-DLC films are good polymeric biomaterialcoatings when deposited on stainless steel and titanium alloyswith or without silicon interfacial layers.
It has been established that boron plays a role in many lifeprocesses, including embryogenesis, bone growth and mainte-nance, immune function and psychomotor skills. Thus, thedelivery of boron by the degradation of borate glass is of spe-cial interest in these fields. For example, boronated materialscan improve the attitude of implants to facilitate healing orto compensate for a lack or loss of bone tissue, particularlyin osteoporotic fractures, where conventional metallic rein-forcements are not applicable because of bone fragility andlow mineral density. In this case, the very good performanceof bioactive glass (e.g., 45S5 Bioglass) is credited to the onsetof spontaneous bonds with the bone tissues through the for-mation of a calcium phosphate (Ca--P) layer [53-55]. The degra-dation of this silicon-based glass was found to be timedependent, and the bulk material remained in the humanbody up to 1 year from implantation [56]. However, cytotoxic-ity of borate glass which arises from rapid release of boron hasto be carefully considered. The incorporation of strontium cansignificantly decrease this phenomenon. Moreover, if conver-sion to apatite is not complete, glass degradation in vivo willnot only render boron a nutritional element for bone health,but will also deliver strontium for new bone formation [57].
5. Boronic acid as a targeting groupin drug/gene delivery
Pendant boronic acids have been reported to enhance thecytosolic delivery of protein toxins [58]. In fact, the cell surfaceis coated with the glycocalyx, a dense layer of polysac-charides [59] and boronic acids readily form esters with the1,2- and 1,3-diols of sugars [60], including those in the glyco-calyx [61,62]. Moreover, boronated functions are compatiblewith human physiology [63,64].
Pendant boronic acids linked to polyethylenimine [65] andto poly(amido amine)s [66] have been shown to enhanceDNA transfection, as it is sketched in Figure 4.
6. Boron neutron capture therapy
BNCT is a tumor treatment based on the incorporation of thestable 10B isotope into cancerous cells. Subsequent irradiationwith a flux of thermal neutrons yields high-energy productswith mean path length in tissues of a few microns. Thisdistance is comparable with typical cell diameters. Therefore,selective destruction of tumors can be achieved without affect-ing nearby healthy tissues [3-6].
An example of tumor selectivity for BNCT applied to livermetastasis is reported in Figure 5.
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Although mercaptoundecahydrododecaborate (BSH;Na2B12H11SH) [67,68] and L-p-boronophenylalanine(L-BPA) [69,70] are currently used in clinical treatment withfairly good outcome, different boron-containing moleculeswith higher BNCT potentiality have been proposed in thelatest 15 years [71]. These include boronated nucleoside [72-76],amino acids and peptides [77,78], sugars [79-82], phospholi-pids [83], tetrapyrroles [84-90] and monoclonal antibodies(mAbs) [91,92]. Moreover, due to the high amount of10B required to induce tumor cell damage (20 -- 35 g/g tumortissue), a variety of vectors have been designed to protectborocompounds from degradation and to improve boronaccumulation in tumors. Examples of well-established drugcarriers include liposomes [93-96], closomers [97,98] and den-drimers [99,100]. Inorganic [101-104] and polymeric nanopar-ticles (micelles) [105,106] have also been prepared and testedon laboratory animals with encouraging results.
An important issue for the success of BNCT is that theboron concentration in surrounding normal tissues and bloodis kept low to minimize radiation damages. To improvetumor selectivity and enhance active targeting boron vectorshave 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 inseveral forms of cancers [114].
7. Expert opinion
A key finding for the use of boron in drug discovery is relatedto its aptitude to replace carbon in many compounds. Boron
versatile chemistry and limited toxicity provide the basis forwidespread biomedical applications. In particular, the abilityof boron to be acceptor of electrons modulates the chemicalproperties of new boron compounds, as it is evidenced inthe case of BNNTs. These structures are bio- and technolog-ical devices of great potential, and are largely unexploredat present.
In recent years, boronated groups have attracted increasinginterest as platforms to obtain new hydrophilic drugs. Deriv-atized borocompounds can be obtained with a variety of func-tions, thus allowing different targets. Noticeable examplesinclude vitamin D receptor ligands, mAbs and epidermalgrowth factor functionalized with the carborane cage.
Until one or two decades ago, most of the synthetic effortswere directed to BNCT, whose primary aim was the localiza-tion of boron into malignant cells. However, this is also thegoal of other boron-containing systems, such as BN nanotubesor boronated molecules with luminescent properties, asdiscussed in this review. Therefore, previously acquired knowl-edge can be, at least partially, translated to different areas ofborocompounds with positive results. On the other hand,newly synthesized molecules, such as luminescent or super-paramagnetic compounds can be of help in solving BNCT-related problems, for example, imaging for boron localization.
Cutting-edge boron applications rely on the study of newclasses of materials both for technological and biological pur-poses. A case in point could be represented by the structuraland physicochemical similarity between carborane and fullerene.This latter was recognized as one of the most promising systemsto be used in nanomedicine since its discovery in 1985 [115].
OB
O
F F
OO
O n
O
H
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.
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The possibility to design novel boronated structures shouldbe fuelled by computational chemistry. Indeed, computationand modeling methods have provided excellent clues forsynthetic strategies in recent years, due to more powerful com-puters and new calculation procedures. The first computationalstudies on boronated systems were performed nearly 20 years
ago [116,117] and, since then, rapid improvement in computertechnology has allowed to obtain novel schemes for obtainingderivatized compounds [9] and multidimentional networks [118].An example where carborane chemistry is used for conjugationwith proteins, and hence for increasing the interactions betweenpharmaceuticals and their targets, is described in [117]. As shown
HO
OO
B
N
NH+
+H3N
Cell
Glycocalix-
-
-
Abbreviated as p(DAB-R)R
70-200 nmpolyplex
R = R = R =
Bz =benzoyl
Benzoyl groups foradditional hydrophobicinteractions with thecell membrane
Phenylboronic acid forcell adhesion throughboronic ester formationwith the glycocalix
2AMPBA =2-aminomethylphenyl-boronic acid
4CPBA =4-carbamaoylphenyl-boronic acid
o-Aminophenylboronicacid for improved celladhesion at reduced pH
O* *
O O30%
+H3N
70%OS S S S
HN
HN
HN
HN
HN
HN
+ HN
+
O NH
O NH
NH
BOHHO
BOH
OH
Cell
Cell membrane
H
B OO
+H3N
N
NNH H+
CellGlycocalix
- -
HN
N NH+
NH+
H+O
+H3N
-
-
--
-
Figure 4. Role of derivatized boronic acid groups in poly(amido amine)s for gene delivery.Adapted from [66] with permission of Elsevier.
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above in this review, carboranes are isosteric with rotating phe-nyl groups, therefore, the substitution of the former with thelatter functions can be carried out in biologically active systems.This may also allow to increase the stability in vivo and thebioavailability of compounds which are normally metabolizedvery rapidly.
To conclude, it is believed that researchers have now theability and the tools for preparing boron-containing molecules
with high potentiality as bioactive agents into a broad field ofmedicinal chemistry.
Declaration of interest
The authors are supported by the Center for Colloidsand Surface Science (CSGI) and by the MIUR (MinisteroIstruzione Universita Ricerca).
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).
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