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Article

1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations

by
Tae-Jin Ha
,
Dong-Kyung Im
,
Seung-Min Kim
and
Jong-Dae Lee
*
Department of Chemistry, College of Natural Sciences, Chosun University, 309 Pilmundaero, Gwangju 61452, Republic of Korea
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(13), 4942; https://doi.org/10.3390/molecules28134942
Submission received: 31 May 2023 / Revised: 16 June 2023 / Accepted: 21 June 2023 / Published: 23 June 2023
(This article belongs to the Section Organometallic Chemistry)
Browse Figures
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Abstract

:
The objective of this study is to design and synthesize substituted η6-chromium(0) tricarbonyl metal complexes carrying o-carborane units as potential boron neutron capture therapy (BNCT) agents. In this study, 1,2-diphenyl-o-carborane (1) units were used as starting materials to generate biologically active species. We investigated how the structural changes of 1 substituted with chromium(0) tricarbonyl affect the biological properties, and 1-(Phenyl-η6-chromium(0) tricarbonyl)-2-phenyl-o-carborane (2) and 1,2-bis(phenyl-η6-chromium(0) tricarbonyl)-o-carborane (3) species were produced in moderate yields. The molecular structures of compounds 1–3 were identified and established by infrared (IR); 1H, 11B, and 13C nuclear magnetic resonance (NMR) and X-ray crystallography analyses. Crystal structures of 1,2-diphenyl-o-carborane and the corresponding chromium complexes 1, 2, and 3 were obtained. In an in vitro study using B16 and CT26 cancer cells containing the triphenyl-o-carboranyl chromium(0) complexes Ph3C2BCr2 and Ph3C2BCr3, which we reported previously, compounds 2 and 3 accumulated at higher levels than compounds Ph3C2BCr2 and Ph3C2BCr3. However, the phenylated o-carboranyl chromium complexes have been found to be more cytotoxic than p-boronophenylalanine (BPA).

Graphical Abstract

1. Introduction

Boron neutron capture therapy (BNCT) is a promising treatment for a variety of central nervous system (CNS) disorders, especially brain tumors. For example, BNCT is currently used as an adjunct to surgery for the treatment of glioblastoma multiforme [1]. The effect of BNCT is to suppress brain micrometastases that cannot be treated surgically or for which other treatment methods are not available [2]. BNCT destroys cancer cells with energy from targeted radiation bursts by reacting boron isotopes delivered to malignant cells with neutrons. Upon uptake into the cells, 10B is externally irradiated with neutrons and becomes unstable [11B]*, decaying to lithium (7Li3+) and releasing high-energy particles (4He2+). Another advantage of boron is that many 10B atoms form a polyhedral cluster, such as B10H102− and B12H122−, enabling a high concentration of boron to be present in the molecule so that a satisfactory therapeutic effect can be expected. The high selectivity of neutron capture by the boron atoms and the effectiveness of treatment using it makes it an acceptable alternative to other chemotherapy methods that destroy cancer cells via high toxicity levels.
Compound o-carborane, namely 1,2-dicarba-closo-dodecaborane, C2B10H12, is a boron-rich compound with an icosahedral structure and a diameter similar to that of a rotating benzene ring, nearly 1 nm, with high symmetry and remarkable stability under various conditions [3]. This cluster contains ten boron and two carbon atoms, making it well-suited as a BNCT agent [4,5], and also has potential in other fields of drug discovery, molecular imaging, and targeted radionuclide therapy [6]. However, despite these advantages, the high toxicity and low water solubility of boron agents remains a significant problem impairing further clinical treatment [7].
Recently, as shown in Figure 1, we reported the successful synthesis and structural characterization of 1,2,3-triphenyl-o-carborane and the corresponding chromium complexes (Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3) [8,9]. Among the transition-metal π-complexes, η6-arene chromium(0) tricarbonyl complexes have been the subject of extensive development due to their significant applications in organic synthesis [10,11]. Moreover, the use of metal carbonyls in bioorganometallic chemistry is being increasingly developed to enhance the potential of chromium complexes [12,13,14,15].
To the best of our knowledge, this is the first example of the application of η6-arene chromium(0) tricarbonyl-substituted o-carborane compounds in BNCT. Until now, few η6-arene chromium(0) tricarbonyl-substituted o-carborane complexes [16,17,18] have been structurally characterized. Moreover, many studies have reported the introduction of various aryl groups to carbons and/or borons in o-carborane. However, no biological characteristics have been reported yet for them. This study is significant because it demonstrates the potential of phenylated o-carboranes with η6-chromium(0) tricarbonyl groups as potential BNCT agents.

2. Results and Discussion

2.1. Synthesis of 1,2-Diphenyl-o-carborane and Corresponding Chromium Metal Complexes

We previously reported the detailed synthesis of the compounds Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3 [8,9]. Compound 1 was synthesized by a procedure modified according to previous results [19,20], as shown in Scheme 1. Compound 1,2-Diphenyl-o-carborane (1) was prepared from decaborane (B10H14) and diphenylacetylene in moderate yield in toluene solvent using N,N-dimethylaniline as a base. As a result, we first synthesized icosahedral o-carborane with phenyl substituents on the two carbons (Scheme 1).
For comparison with previous results, we tried to confirm the electron-withdrawing ability of o-carborane by reacting chromium(0) hexacarbonyl [Cr(CO)6] with two phenyl groups introduced into o-carborane [21]. The reaction of 1 with Cr(CO)6 produced η6-phenyl-coordinated mono- and bis-chromium complexes (2 and 3) in moderate yields through stoichiometric reactions, as shown in Scheme 2. Interestingly, these results showed that 1,2-diphenyl-o-carborane (1) prefers stoichiometric reactions to 1,2,3-triphenyl-o-carborane.

2.2. IR and NMR Spectroscopy

The structure of 1,2-diphenyl-o-carborane (1) was proposed based on the assignments of the 1H, 11B, and 13C NMR resonances before confirmation by X-ray diffraction (XRD). The 1H NMR spectrum of compound 1 showed resonances at around δ 7.45~7.15 for the two phenyl rings. The 11B NMR spectrum showed resonances at around δ −11.38~−2.40. The 13C NMR spectrum showed resonances at around δ 130.55~85.16. The infrared (IR) spectra of compounds 2 and 3 showed characteristic absorption bands of C≡O units at 1965, 1890 (2), 1965, and 1892 cm−1 (3). These values are lower than those of (C6H6)Cr(CO)3 [22,23,24,25,26]. The IR and NMR spectra clearly indicate Cr coordination with the phenyl groups of 2 and 3, with chemical shifts to the downfield region of δ 7.715–7.250 and 137.55–130.06 in the 1H and 13C NMR spectra, respectively (see Figures S1–S9 in Supplementary Materials).

2.3. X-ray Structural Studies of 1,2-Diphenyl-o-carborane and Corresponding Chromium Complexes

The selected crystallographic data and a summary of the intensity data collection parameters for 1, 2, and 3 are presented in Table 1 and Table 2, respectively. Detailed information on the structural determinations and structural features of compounds 1, 2, and 3 are provided in the Supplementary Materials and Appendix A. Additionally, the molecular structures and structural characteristics of Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3 are also included (Figures S1–S3 and Tables S10 and S11). Single-crystal X-ray structure determination revealed the structural authenticity of each compound and suggested alterations to the electronic structure based on the changes in the C–C distance of o-carborane cage [27]. The C1–C2 bond distance of 1 was 1.726(2) Å, which is significantly longer than the C1–C2 bond distance of the unsubstituted o-carborane [1.629(6) and 1.630(6) Å]. Moreover, our comparison of the C–C distances in compounds 1 and Ph3C2B (Table S11) showed that the bonds in Ph3C2B were slightly longer than those in compound 1. Compound Ph3C2B contained further phenyl decorations at the boron atom while maintaining the active compound 1 platform [28,29].
Single crystals of 1 and its chromium(0) tricarbonyl complexes, 2 and 3, suitable for X-ray crystallography, were obtained from dichloromethane solutions by slow evaporation. The general structural characteristics of compound 1 and its chromium complex are shown in Table 2. The molecular structures of compounds 1, 2, and 3 are shown in Figure 2, Figure 3 and Figure 4. Compound 1 was reported in 1993 by Lewis and Welch (C14H20B10, Mw = 296.41, monoclinic, P21/c, a = 10.832(4), b = 24.890(13), c = 13.9243(21) Å, β = 111.881(21)°, V = 3483.6 Å3, Z = 8) [30]. By comparing the data, it can be seen that the bond lengths, angles, and dihedral angles were nearly identical (Figure 2).
As shown in Figure 3, the chromium atom of compound 2 was coordinated to the phenyl ring of the carbon atom of o-carborane via a π-bond, similar to the previous results [8,9]. The chromium metal adopted the typical three-legged “piano stool” geometry, with the expected geometrical parameters. The chromium metals were centered approximately over the phenyl rings, giving rise to Cr1–C6H5 face (centroid) distances of 1.702 Å. The average C–C bond length in the coordinated phenyl ring was 1.410 Å, 0.028 Å longer than the average bond length of 1.382 Å for C–C bonds within the non-coordinated phenyl ring. The Cr–CPh and Cr–CO bonds had average values of 2.210 and 1.856 Å, respectively, which were within the normal range [31]. The average C–O bond length in the chromium-coordinated carbonyl ligands was 1.143 Å, slightly shorter than that of the reported η6-arene chromium(0) tricarbonyl complexes [32,33,34,35,36]. As expected, the C1–C2 bond distance was 1.740(2) Å, slightly greater than compound 1, and was essentially in the range of non-bonding character [37,38,39,40]. Furthermore, as shown in Table 2 and Table S6, the torsion angles of the two phenyl rings of 1 and 2 changed upon coordination with the chromium atom.
The X-ray crystal structure of 3 (Figure 4) reveals that the dichromium atoms adopted an η6-coordination with the two phenyl rings. The single crystal X-ray diffraction study of 3 revealed crystallization in the triclinic space group P-1. Interestingly, even though it was a triclinic space group, the APEX3 program identified the Z value as 8, which made it difficult to solve. For this reason, we attempted to obtain better results by changing the crystal system and the space group, but we were unable to obtain satisfactory results. In the end, this was considered to be recognized by four molecules as one molecule in the unit cell, and the structure was interpreted by adjusting the Z value to 2. The geometrical parameters of complex 3 were within the expected ranges (Table 2). The average C–C bond length in the chromium-coordinated phenyl rings was 1.406 Å, 0.03 Å longer than the average bond length of 1.376 Å for the C–C bonds in 1. The Cr–CPh and Cr–CO bond lengths were within the normal range [31], with average values of 2.212 and 1.851 Å, respectively. The average C–O bond length in the chromium-coordinated carbonyl ligands was 1.138 Å, significantly shorter than the lengths of reported η6-arene chromium(0) tricarbonyl complexes [32,33,34,35,36]. As shown in Table 2, the chromium metals were centered approximately over the phenyl rings, giving rise to Cr1/Cr2–C6H5 face (centroid) distances of 1.687 and 1.705 Å, respectively. Interestingly, the C1–C2 bond length of 3 was shorter than that of 1 and 2. It was shown that the contraction of this bond was due to a favorable phenyl ring π*, and carboranyl σ* orbital interactions did not occur in 3, as has been observed in previous results [8,9]. As shown in Table 2 and Table S9, the torsion angles of the phenyl rings of 1 and 3 or 2 and 3 changed upon coordination with the chromium atoms.

2.4. Determination of IC50 and Incorporation of Boron into B16 and CT26 Cells

B16 mouse melanoma and CT26 colon carcinoma cells were treated with compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 for 72 h, after which the cell viability was determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 showed higher cytotoxicity than BPA (Table 3), with IC50 (the half maximal inhibitory concentration) values in the range of 0.091–0.736 μM. Interestingly, the 1,2,3-triphenyl-o-carboranyl chromium(0) tricarbonyl complexes (Ph3C2BCr2 and Ph3C2BCr3) showed higher cytotoxicity to the B16 and CT26 cells than complexes 2 and 3. The higher cytotoxicity of compounds Ph3C2BCr2 and Ph3C2BCr3 to B16 cells may be a result of the difference in the mechanism by which the phenyl groups and chromium(0) tricarbonyl moieties induce cell toxicity. Compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 exhibited similar activities in the CT26 and B16 cells, with IC50 values in the range of 0.089–0.833 μM.
We next examined the level of intracellular accumulation of compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 by determining their boron concentrations using ICP-OES. The intracellular boron uptake of compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 in B16 and CT26 cells was higher than that of BPA (Table 3). Boron uptake from both bis- and tris-chromium(0) tricarbonyl-substituted compounds, which included the 1,2,3-triphenyl-o-carboranyl chromium tricarbonyl complexes (i.e., Ph3C2BCr2 and Ph3C2BCr3), was lower. These results show that the introduction of phenyl groups or chromium metals into the carborane backbone increases cytotoxicity rather than increasing boron accumulation in cancer cells.

3. Materials and Methods

3.1. General Procedure

All manipulations were performed under either a dry nitrogen or argon atmosphere using standard Schlenk techniques. Tetrahydrofuran (THF) was distilled from sodium and benzophenone under a nitrogen atmosphere. Elemental analyses were performed using a Carlo Erba Instruments CHNS-O EA 1108 analyzer. High-resolution tandem mass spectrometry (JMS-HX 110/110A, Jeol Ltd.) data were acquired at the Korean Basic Science Institute. 1H, 11B, and 13C NMR spectra were recorded using a Bruker 600 spectrometer operating at 600.1, 150.9, and 192.6 MHz, respectively. All 11B chemical shifts were referenced to BF3·O(C2H5)2 (0.0 ppm), with a negative sign indicating an upfield shift. All proton and carbon chemical shifts were measured relative to the internal residual CHCl3 in the lock solvent (99.9% CDCl3). Decaborane was purchased from Katchem. N,N-dimethylaniline, 1,2-diphenylacetylene, n-BuLi (2.5 M in hexane), and chromium hexacarbonyl [Cr(CO)6] were purchased from Aldrich Chemicals.

3.2. Crystal Structure Determination

Crystals of 1, 2, and 3 were obtained from toluene or CH2Cl2, sealed in glass capillaries under argon atmosphere, and mounted on a diffractometer. Preliminary examination and data collection were performed using a Bruker SMART CCD detector system single-crystal X-ray diffractometer equipped with a sealed-tube X-ray source (40 kV × 50 mA), using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The preliminary unit cell constants were determined using a set of forty-five narrow-frame (0.3° in ω) scans. Double-pass scanning was used to exclude noise. The collected frames were integrated using an orientation matrix determined from the narrow-frame scans. The SMART software package was used for data collection and SAINT was used for frame integration [41]. The final cell constants were determined by global refinement of the xyz centroids of the reflections harvested from the entire dataset. Structure solution and refinement were performed using the SHELXTL-PLUS software package [42].

3.3. Cell Viability Assay (MTT Assay)

B16 and CT26 cells were obtained from the Bioevaluation Center of the Korea Research Institute of Bioscience and Biotechnology, Korea. B16 and CT26 cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Welgene, Gyeongsan-si, Republic of Korea) containing 10% fetal bovine serum (FBS; Welgene). The cells were cultured at 37 °C in an incubator with 5% CO2. The boron compounds were dissolved in dimethylsulfoxide (DMSO), and the resulting solution was diluted with Dulbecco’s modified Eagle’s medium (DMEM) (10% FBS), or p-boronophenylalanine (BPA) was directly dissolved in the same medium. In a 96-well culture plate (Falcon 3072), B16 mouse melanoma and CT26 colon carcinoma cells (5 × 103 cells/well) were cultured in five wells with a medium containing the boron compounds at various concentrations. This was followed by incubation for 72 h at 37 °C in a CO2 incubator. DMSO is non-toxic at concentrations less than 0.5%, and control experiments confirmed the non-toxicity of DMSO at the concentrations used in the present experiments. After incubation, the medium was removed, the cells were washed three times with phosphate-buffered saline [PBS (–)], and the CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay (MTT) was used to count the cells on a microplate reader. The concentration that resulted in a cell culture with 50% of the number of cells in the corresponding untreated group (IC50) is summarized in Table 3.

3.4. In Vitro Boron Incorporation into B16 and CT26 Cancer Cells

B16 and CT26 cancer cells were cultured in Falcon 3025 dishes (150 mm in diameter). When the cell population increased to fill the dish (5 × 105 cells/dish), the boron compounds and BPA (10 μM) were added to the dishes. The cells were then incubated for 3 h at 37 °C in DMEM (20 mL of 10% FBS). The cells were washed three times with Ca/Mg-free PBS (–), collected with a rubber policeman, digested with a mixture of 60% HClO4–30% H2O2 (1:2) solution (2 mL), and finally, decomposed for 1 h at 75 °C. After filtration through a membrane filter (Millipore, 0.22 mm), the boron concentration was determined using an inductively coupled plasma optical emission spectroscopy (ICP-OES) instrument (Avio 220 Max, PerkinElmer, Waltham, MA, USA). Each experiment was performed in triplicate.

3.5. Synthesis of 1,2-Diphenyl-o-carborane (1)

Compounds 1,2-Diphenylethyne (2.2 g, 12.0 mmol) and B10H14 (decaborane) (1.22 g, 10.0 mmol) were dissolved in dry toluene (100 mL) at room temperature under an argon atmosphere. N,N-dimethylaniline (2.78 mL, 24.0 mmol) was added to the reaction mixture, and the mixture was stirred at 110 °C for 24 h. After cooling, the solid residue was filtered off and the solvent was evaporated to dryness. The crude mixture was purified using silica gel column chromatography (hexane as the eluent, Rf = 0.15). Recrystallization from CH2Cl2 provided 1 as colorless crystals (2.31 g, 78%). HRMS: calculated for [12C141H2011B10]+ 296.2568. Found: 296.2571. IR spectrum (KBr pellet, cm−1): ν(CAr–H) 3024, ν(B–H) 2589, ν(C=CAr) 1601, 1500. 1H NMR (CDCl3, 600 MHz) δ 7.45 (d, 4H, J = 7.8 Hz, Ph-H), 7.24 (t, 2H, J = 7.2 Hz, Ph-H), 7.15 (t, 4H, J = 7.8 Hz, Ph-H). 11B{1H} NMR (CDCl3, 192.6 MHz) δ −2.40, −9.09, −10.37, −11.38. 13C NMR (CDCl3, 150.9 MHz) δ 130.55, 130.10, 128.21 (Ph), 85.16 (Ccab).

3.6. Synthesis of 1-(Phenyl-η6-chromium(0) tricarbonyl)-2-phenyl-o-carborane (2)

Compound 1 (0.3 g, 1.0 mmol) and 1.2 equiv of [Cr(CO)6] (0.26 g, 1.2 mmol) were dissolved in a mixture of THF (5 mL) and di-n-butyl ether (50 mL). The mixture was refluxed for 72 h. The resulting dark reddish solution was cooled to room temperature and filtered through Celite. The solvent was evaporated under reduced pressure. After evaporation, the crude reaction mixture was purified by column chromatography [CH2Cl2:hexane (1:1) as the eluent, Rf = 0.3~0.35] to give the chromium complex 2, which was then recrystallized from toluene to obtain red crystals. Yield: 88% (0.38 g, 0.88 mmol). HRMS: calculated for [12C171H2011B1052Cr116O3]+ 432.1821. Found: 432.1824. IR spectrum (KBr pellet, cm−1): ν(CAr–H) 3023, 3020, ν(B–H) 2588, ν(C≡O) 1965,1890. 1H NMR (CDCl3, 600.1 MHz) δ 7.627 (d, 3H, J = 7.2 Hz, Ph-H), 7.512 (t, 2H, J = 7.2 Hz, Ph-H), 7.454 (t, 1H, J = 7.2 H, Ph-H), 7.346 (t, 2H, J = 7.2 Hz, Ph-H), 7.250 (t, 2H, J = 7.8 Hz, Ph-H). 11B NMR (CDCl3, 192.6 MHz) δ −0.82, −2.88, −4.75, −9.77, −11.05, −14.04. 13C NMR (CDCl3, 150.9 MHz) δ 221.54 (Cr−CO), 137.34, 133.50, 132.19, 131.60, 131.51, 130.16, 130.06 (Ph), 87.54 (Ccab).

3.7. Synthesis of 1,2-bis(phenyl-η6-chromium(0) tricarbonyl)-o-carborane (3)

A procedure analogous to the preparation of 2 was used to obtain red crystals. Yield: 57% (0.32 g, 0.57 mmol). HRMS: calculated for [12C201H2011B1052Cr216O6]+ 568.1073. Found: 568.1077. IR spectrum (KBr pellet, cm−1): ν(CAr–H) 3021, ν(B–H) 2583, 2589; ν(C≡O) 1965, 1892. 1H NMR (CDCl3, 600.1 MHz) δ 7.715 (d, 4H, J = 7.8 Hz, Ph-H), 7.497 (t, 2H, J = 7.2 Hz, Ph-H), 7.406 (t,, 4H, J = 7.8 Hz, Ph-H). 11B NMR (CDCl3, 192.6 MHz) δ −2.50, −9.49, −11.07, −11.83. 13C NMR (CDCl3, 150.9 MHz) δ 228.85 (Cr-CO), 137.55, 136.15, 134.31 (Ph), 87.17 (Ccab).

4. Conclusions

In conclusion, this study describes the synthesis, X-ray structures, and biological activities of a series of 1,2-diphenyl- and 1,2,3-triphenyl-o-carborane compounds and their corresponding chromium(0) tricarbonyl transition metal complexes, which can be easily stoichiometrically substituted with transition metals to produce highly active biological molecules for BNCT. We presented a general and versatile method for the sequential introduction of phenyl groups into o-carborane and stoichiometrically-coordinated transition metal complexes using chromium(0) hexacarbonyl. Interestingly, it was confirmed that the C1–C2 bond length of compound 1 was the longest in compound 2 and the shortest in compound 3. We found that this affected the interaction of the π* orbital of the phenyl group with the σ* orbital of the carborane carbon by functioning as a strong π-receptor to form stable new types of organometallic complexes (2 and 3) through metal(Cr)-to-ligand(Ph) back-bonding interactions. The results clearly show the electron withdrawal properties of the o-carborane when the two phenyl groups are placed face-to-face with each other. Diphenyl- or triphenyl-o-carborane and the corresponding chromium complexes showed higher cytotoxicity than p-boronophenylalanine in B16 and CT26 cancer cell lines; however, boron accumulation was higher than that of p-boronophenylalanine. As a result, it was confirmed that as more chromium metal atoms and/or phenyl groups were substituted in the o-carborane backbone, cytotoxicity increased, but boron accumulation decreased.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28134942/s1, Figures S1–S9: NMR spectra of compounds 1, 2, and 3; Figures S10–S12: Molecular structures of Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3; Tables S1–S9: Bond lengths (Å), angles (°), and torsion angles (°) of compounds 1, 2, and 3; Tables S10 and S11: Crystal data and structure refinement and comparison of selected bond lengths (Å), angles (°), and torsion angles (°) for 1–3 and Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3.

Author Contributions

Conceptualization, J.-D.L.; chemical experiments, T.-J.H., D.-K.I. and S.-M.K.; designed and performed biological tests, D.-K.I. and J.-D.L.; validation, J.-D.L.; formal analysis, T.-J.H., D.-K.I. and S.-M.K.; investigation, T.-J.H., D.-K.I. and S.-M.K.; data curation, T.-J.H. and J.-D.L.; writing—original draft preparation, T.-J.H. and S.-M.K.; writing—review and editing, J.-D.L.; supervision, J.-D.L.; project administration, J.-D.L.; funding acquisition, J.-D.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Supplementary Materials are available online. Figures S1–S6: X-ray structures of compounds 1, 2, 3, Ph3C2B, Ph3C2BCr2 and Ph3C2BCr3, Tables S1–S6. Detailed information on the structural determinations and structural features of compounds 1, 2, 3, Ph3C2B, Ph3C2BCr2 and Ph3C2BCr3 are provided in the Supplementary Materials.

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1F1A1074095).

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

CCDC 2262119, 2262120, and 2262121 contain supplementary crystallographic data for compounds 1, 2, and 3, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html, (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033; or [email protected]). Additional Supporting Information can be found online in the Supporting Information tab.

References

  1. Yamamoto, T.; Nakai, K.; Matsumura, A. Boron neutron capture therapy for glioblastoma. Cancer Lett. 2008, 262, 143–152. [Google Scholar] [CrossRef]
  2. Pisarev, M.A.; Dagrosa, M.A.; Juvenal, G.J. Boron neutron capture therapy in cancer: Past, present and future. Arq Bras Endocrinol Metab. 2007, 51, 852–856. [Google Scholar] [CrossRef] [Green Version]
  3. Lesnikowski, Z.J. Boron units as pharmacophores—New applications and opportunities of boron cluster chemistry. Collect. Czech. Chem. Commun. 2007, 72, 1646–1658. [Google Scholar] [CrossRef]
  4. Tjarks, W.; Tiwari, R.; Byun, Y.; Narayanasamy, S.; Barth, R.F. Carboranyl thymidine analogues for neutron capture therapy. Chem. Commun. 2007, 4978–4991. [Google Scholar] [CrossRef] [PubMed]
  5. Bregadze, V.I.; Sivaev, I.B. Polyhedral Boron Compounds for BNCT in Boron Science: New Technologies and Applications; CRC Press: Boca Raton, FL, USA, 2011; Chapter 9; pp. 187–207. [Google Scholar]
  6. Armstrong, A.F.; Valliant, J.F. The bioinorganic and medicinal chemistry of carboranes: From new drug discovery to molecular imaging and therapy. Dalton Trans. 2007, 38, 4240–4251. [Google Scholar] [CrossRef] [PubMed]
  7. Korbe, S.; Schreiber, P.J.; Michl, J. Chemistry of the Carba-closo-dodecaborate(−) Anion, CB11H12−. Chem. Rev. 2006, 106, 5208–5249. [Google Scholar] [CrossRef]
  8. Jin, G.F.; Hwang, J.-H.; Lee, J.-D.; Wee, K.-R.; Suh, I.-H.; Kang, S.O. A three-dimensional π-electron acceptor, tri-phenyl-o-carborane, bearing a rigid conformation with end-on phenyl units. Chem. Commun. 2013, 49, 9398–9400. [Google Scholar] [CrossRef]
  9. Kim, S.-Y.; Ma, S.-Y.; Kang, S.O.; Lee, J.-D. B-phenylated o-carboranes and its chromium derivatives: Synthesis, electrochemical properties, and X-ray structural studies. J. Organomet. Chem. 2018, 865, 100–108. [Google Scholar] [CrossRef]
  10. Semmelhack, M.F. Transition Metal Arene Complexes: Nucleophilic Addition, Comprehensive Organometallic Chemistry II; Abel, E.W., Stone, F.G.A., Wilkinson, G., Eds.; Pergamon Press: Oxford, UK, 1995; Volume 12, pp. 979–1013. [Google Scholar]
  11. Rose-Munch, F.; Rose, E. Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley: Hoboken, NJ, USA, 2002; Chapter 11; pp. 368–397. [Google Scholar]
  12. Jonson, T.R.; Mann, B.E.; Clark, J.E.; Foresti, R.; Green, C.J.; Motterlini, R. Metal Carbonyls: A New Class of Pharmaceuticals? Angew. Chem. Int. Ed. 2003, 42, 3722–3729. [Google Scholar] [CrossRef]
  13. Jaouen, G.; Vessières, A.; Butler, I. Bioorganometallic Chemistry: A Future Direction for Transition Metal Organometallic Chemistry? Acc. Chem. Res. 1993, 26, 361–369. [Google Scholar] [CrossRef]
  14. Hess, A.; Metzler-Nolte, N. Transition metal labels on peptide nucleic acid (PNA) monomers. Chem. Commun. 1999, 885–886. [Google Scholar] [CrossRef]
  15. Baldoli, C.; Maiorana, S.; Licandro, E.; Zinzalla, G.; Perdicchia, D. Synthesis of Chiral Chromium Tricarbonyl Labeled Thymine PNA Monomers via the Ugi Reaction. Org. Lett. 2002, 4, 4341–4344. [Google Scholar] [CrossRef]
  16. Zakharkin, L.I.; Zhigareva, G.G. Synthesis of o- and m-carboranylbenzenechromotricarbonyls by the reaction of lithium o- and m-carboranes with chlorobenzenechromotricarbonyl. Zhurnal Obshchei Khimii 1983, 53, 953–954. [Google Scholar]
  17. Vasyukova, N.I.; Nekrasov, Y.S.; Sukharev, Y.N.; Magomedov, G.K.; Frenkel, A.S. Mass spectrometry of π-complexes of transition metals. 33. Carboranyl derivatives of benzenechromium tricarbonyl. Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1985, 1548–1549. [Google Scholar] [CrossRef]
  18. Magomedov, G.K.; Frenkel, A.S.; Kalinin, V.N.; Zakharkin, L.I. Synthesis of arylcarboranechromiumtricarbonyls. Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1977, 949–952. [Google Scholar]
  19. Ohta, K.; Goto, T.; Endo, Y. 1,2-Dicarba-closo-dodecaboran-1-yl Naphthalene Derivatives. Inorg. Chem. 2005, 44, 8569–8573. [Google Scholar] [CrossRef]
  20. Kokado, K.; Nagai, A.; Chujo, Y. Poly(γ-glutamic acid) Hydrogels with Water-Sensitive Luminescence Derived from Aggregation-Induced Emission of o-Carborane. Macromolecules 2010, 43, 6463–6468. [Google Scholar] [CrossRef]
  21. Henly, T.J.; Knobler, C.B.; Hawthorne, M.F. Reactions of Anionic Carborane Nucleophiles with Chromium-Coordinated Haloarenes. Organometallics 1992, 11, 2313–2316. [Google Scholar] [CrossRef]
  22. Mahaffy, C.A.L.; Pauson, P.L. (η6-Arene)tricarbonylchromium Complexes. Inorg. Synth. 1979, 19, 154–158. [Google Scholar]
  23. Fischer, R.D. IR-spektroskopische Untersuchungen der ν-CO-Banden an Metallcarbonylkomplexen rnit zentrisch-x-gebundenen organischen Ringsystemen. Chem. Ber. 1960, 93, 165–175. [Google Scholar] [CrossRef]
  24. Brown, D.A.; Sloan, H. Molecular-orbital Theory of Organometallic Compounds. Part I V.l Substitution Reactions of Tricarbonylbenzenechromium. J. Chem. Soc. 1963, 4389–4394. [Google Scholar] [CrossRef]
  25. Brown, D.A.; Raju, J.R. Infrared and Proton Magnetic Resonance Spectra of π-Complexes of Substituted Condensed Hydrocarbons. J. Chem. Soc. A. 1966, 1617–1620. [Google Scholar] [CrossRef]
  26. Adams, D.M.; Squire, A. Vibrational Spectra of Some Monosubstituted-π-arene Tricarbonylchromium Complexes and of Methyl Benzoate. J. Chem. Soc. Dalton Trans. 1974, 6, 558–565. [Google Scholar] [CrossRef]
  27. Fox, M.A.; Nervi, C.; Crivello, A.; Low, P.J. Carborane radical anions: Spectroscopic and electronic properties of a carborane radical anion with a 2n + 3 skeletal electron count. Chem. Commun. 2007, 23, 2372–2374. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Boyd, L.A.; Clegg, W.; Copley, R.C.B.; Davidson, M.G.; Fox, M.A.; Hibbert, T.G.; Howard, J.A.K.; Mackinnon, A.; Peace, R.J.; Wade, K. Exo-π-bonding to an ortho-carborane hypercarbon atom: Systematic icosahedral cage distortions reflected in the structures of the fluoro-, hydroxy- and amino-carboranes, 1-X-2-Ph-1,2-C2B10H10 (X = F, OH or NH2) and related anions. Dalton Trans. 2004, 17, 2786–2799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Fox, M.A.; Peace, R.J.; Clegg, W.; Elsegood, M.R.J.; Wade, K. Trends in ortho-carboranes 1-X-2-R-1,2-C2B10H10 (R = Ph, Me) bearing an exo-CN-bonded substituent group (X = NO, N=NRʹ or NHRʺ). Polyhedron 2009, 28, 2359–2370. [Google Scholar] [CrossRef] [Green Version]
  30. Lewis, Z.G.; Welch, A.J. Structure of 1,2-Diphenylcarbaborane, 1,2-Ph2-1,2-closo-C2B10H10. Acta Crystallogr. Sect. C. 1993, 49, 705–710. [Google Scholar] [CrossRef]
  31. Calhorda, M.J.; Frazão, C.F.; Martinho-Simões, J.A. Metal-Carbon “Bond Strengths” in Cr(CO)6, Cr(η-C6H6)2, and Cr(CO)3(η-C6H6). J. Organomet. Chem. 1984, 262, 305–314. [Google Scholar] [CrossRef]
  32. Rees, B.; Coppens, P. Electronic Structure of Benzene Chromium Tricarbonyl by X-ray and Neutron Diffraction at 78 ºK. Acta Crystallogr. Sect. B 1973, 29, 2516–2528. [Google Scholar] [CrossRef] [Green Version]
  33. Bailey, M.F.; Dahl, L.F. Three-Dimensional Crystal Structure of Benzenechromium Tricarbonyl with Further Comments on the Dibenzenechromium Structure. Inorg. Chem. 1965, 4, 1314–1319. [Google Scholar] [CrossRef]
  34. Wang, Y.; Angermund, K.; Goddard, R.; Kruger, C. Redetermination of the Experimental Electron Deformation Density of Benzenetricarbonylchromium. J. Am. Chem. Soc. 1987, 109, 587–589. [Google Scholar] [CrossRef]
  35. Czerwinski, C.J.; Guzei, I.A.; Riggle, K.M.; Schroeder, J.R.; Spencer, L.C. Haptotropic rearrangement in tricarbonylchromium complexes of 2-aminobiphenyl and 4-aminobiphenyl. Dalton Trans. 2011, 40, 9439–9446. [Google Scholar] [CrossRef] [PubMed]
  36. Guzei, I.A.; Spencer, L.C.; Buechel, S.C.; Kaufmann, L.B.; Czerwinski, C.J. Intricacies of ligand coordination in tricarbonylchromium(0) complexes with ortho- and para-fluorobiphenyls. Acta Crystallogr. Sect. C 2017, 73, 638–644. [Google Scholar] [CrossRef]
  37. Davidson, M.G.; Hibbert, T.G.; Howard, J.A.K.; Mackinnon, A.; Wade, K. Definitive crystal structures of ortho-, meta- and para-carboranes: Supramolecular structures directed solely by C−H···O hydrogen bonding to hmpa (hmpa = hexamethylphosporamide). Chem. Commun. 1996, 2285–2286. [Google Scholar] [CrossRef]
  38. Llop, J.; Viñas, C.; Oliva, J.M.; Teixidor, F.; Flores, M.A.; Kivekäs, R.; Sillanpää, R. Modulation of the C−C distance in disubstituted 1,2-R2-o-carboranes. Crystal structure of closo 1,2-(SPh)2-1,2-C2B10H10. J. Organomet. Chem. 2002, 657, 232–238. [Google Scholar] [CrossRef]
  39. Oliva, J.M.; Allan, N.L.; Schleyer, P.v.R.; Viñas, C.; Teixidor, F. Strikingly Long C···C Distances in 1,2-Disubstituted ortho-Carboranes and Their Dianions. J. Am. Chem. Soc. 2005, 127, 13538–13547. [Google Scholar] [CrossRef]
  40. Hutton, B.W.; Maclntosh, F.; Ellis, D.; Herisse, F.; Macgregor, S.A.; McKay, D.; Petrie-Armstrong, V.; Rosair, G.M.; Perekalin, D.S.; Tricas, H.; et al. Unprecedented steric deformation of ortho-carborane. Chem. Commun. 2008, 42, 5345–5347. [Google Scholar] [CrossRef]
  41. Bruker Analytical X-ray Division, SMART and SAINT; Bruker: Madison, WI, USA, 2002.
  42. Sheldrick, G.M. Bruker Analytical X-Ray Division, SHELXTL-PLUS Software Package; Bruker: Madison, WI, USA, 2002. [Google Scholar]
Molecules 28 04942 g001 550
Figure 1. Molecular structure of 1,2,3-triphenyl-o-carborane and its chromium(0) tricarbonyl complexes Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3.
Figure 1. Molecular structure of 1,2,3-triphenyl-o-carborane and its chromium(0) tricarbonyl complexes Ph3C2B, Ph3C2BCr2, and Ph3C2BCr3.
Molecules 28 04942 g001
Molecules 28 04942 sch001 550
Scheme 1. Preparation of 1, 2-diphenyl-o-carborane (1).
Scheme 1. Preparation of 1, 2-diphenyl-o-carborane (1).
Molecules 28 04942 sch001
Molecules 28 04942 sch002 550
Scheme 2. Preparation of mono- and bis-chromium complexes (2 and 3).
Scheme 2. Preparation of mono- and bis-chromium complexes (2 and 3).
Molecules 28 04942 sch002
Molecules 28 04942 g002 550
Figure 2. ORTEP drawing (30% probability for thermal ellipsoids) of 1 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron).
Figure 2. ORTEP drawing (30% probability for thermal ellipsoids) of 1 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron).
Molecules 28 04942 g002
Molecules 28 04942 g003 550
Figure 3. ORTEP drawing (30% probability for thermal ellipsoids) of 2 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron, blue = chromium, red = oxygen).
Figure 3. ORTEP drawing (30% probability for thermal ellipsoids) of 2 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron, blue = chromium, red = oxygen).
Molecules 28 04942 g003
Molecules 28 04942 g004 550
Figure 4. ORTEP drawing (30% probability for thermal ellipsoids) of 3 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron, blue = chromium, red = oxygen).
Figure 4. ORTEP drawing (30% probability for thermal ellipsoids) of 3 (the hydrogen atoms are omitted for clarity) (black = carbon, green = boron, blue = chromium, red = oxygen).
Molecules 28 04942 g004
Table
Table 1. Crystal data and structure refinement of 1–3.
Table 1. Crystal data and structure refinement of 1–3.
123
Identification codeK120504K130805K131105
Empirical formulaC14H20B10C17H20B10Cr1O3C20H20B10Cr2O6
Formula weight296.40432.43568.46
Temperature293(2) K293(2) K293(2) K
Wavelength0.71073 Å0.71073 Å0.71073 Å
Crystal system, space groupMonoclinic, P21/nMonoclinic, P21/nTriclinic, Pī
Unit cell dimensionsa = 10.859(1) Åa = 10.621(3) Åa = 17.540(2) Å, α = 105.746(2)°
b = 24.953(3) Å, β = 111.854(2)°b = 17.056(5) Å, β = 106.622(5)°b = 18.060(2) Å, β = 110.226(2)°
c = 13.938(2) Åc = 12.174(4) Åc = 19.484(3) Å, γ = 91.256(2)°
Volume3505.3(8)2113.2(1)5528.0(1)
Z, Dcalc8, 1.1234, 1.3592, 0.342
F(000)1232.0880.0572
Crystal size0.15, 0.13, 0.120.17, 0.15, 0.130.20, 0.20, 0.15
θ range for data collection1.63 to 28.372.12 to 28.461.17 to 28.38
Limiting indices−14 ≤ h ≤ 14, −33 ≤ k ≤ 32, −18 ≤ l ≤ 18−14 ≤ h ≤ 14, −22 ≤ k ≤ 22, −16 ≤ l ≤ 16−23 ≤ h ≤ 23, −24 ≤ k ≤ 24, −26 ≤ l ≤ 25
Reflections collected/unique35826/8726 [R(int) = 0.0421]28490/5305 [R(int) = 0.0238]44259/18014 [R(int) = 0.0398]
Completeness to θ = 28.3899.3%99.2%65.0%
Refinement methodFull-matrix least-squares on F2Full-matrix least-squares on F2Full-matrix least-squares on F2
Data/restraints/parameters8726/0/5815305/0/36018014/0/1409
Goodness-of-fit on F21.0081.0530.902
Final R indices [I > 2θ(I)]a R1 = 0.0616, b wR2 = 0.1545a R1 = 0.0332, b wR2 = 0.0958a R1 = 0.0563, b wR2 = 0.1505
R indices (all data)a R1 = 0.1037, b wR2 = 0.1897a R1 = 0.0388, b wR2 = 0.1018a R1 = 0.0877, b wR2 = 0.1612
Largest diff. peak and hole0.220 and −0.355 e.Å−30.364 and −0.242 e.Å−30.687 and −0.375 e.Å−3
a R1 = ∑||Fo| − |Fc|| (based on reflections with Fo2 > 2σF2), b wR2 = [∑[w(Fo2-Fc2)2]/∑[w(Fo2)2]]1/2; w = 1/[σ2(Fo2) + (0.095P)2]; P = [max(Fo2, 0) + 2Fc2]/3(also with Fo2 > 2σF2).
Table
Table 2. Comparison of selected bond lengths (Å), angles (°), and torsion angles (°) for 1–3.
Table 2. Comparison of selected bond lengths (Å), angles (°), and torsion angles (°) for 1–3.
Molecules 28 04942 i001Molecules 28 04942 i002Molecules 28 04942 i003
PhC−C (av)1.3761.4001.406
PhC−C (av)−Cr 2.2102.212
CabC−C1.726(2)1.740(2)1.724(4)
Cent−Cr 1.7021.696(av)
Cr–CO 1.856(av)1.851(av)
C1–C131.507(2)1.499(2)1.502(4)
C2–C191.501(2)1.500(2)1.510(4)
C13–C1–C2118.3(1)116.6(1)116.4(2)
C19–C2–C1119.0(1)119.6(1)116.1(2)
C1-C2-C19-C2084.1(2)86.1(2)105.8(3)
C2-C1-C13-C1481.7(2)102.3(1)112.4(3)
Table
Table 3. Cytotoxicity (IC50) and boron accumulation of B16 melanoma and CT26 colon carcinoma cells.
Table 3. Cytotoxicity (IC50) and boron accumulation of B16 melanoma and CT26 colon carcinoma cells.
CompoundsB16CT26
Cytotoxicity IC50 (M) aBoron Accumulation (ppm) bCytotoxicity IC50 (M) aBoron Accumulation (ppm) b
20.736 × 10−6 (±0.01)0.825 ± 0.0030.833 × 10−6 (±0.03)0.755 ± 0.009
30.681 × 10−6 (±0.04)0.620 ± 0.0020.314 × 10−6 (±0.07)0.694 ± 0.002
Ph3C2BCr20.411 × 10−6 (±0.06)0.384 ± 0.0060.164 × 10−6 (±0.05)0.402 ± 0.002
Ph3C2BCr30.091 × 10−6 (±0.03)0.221 ± 0.0010.089 × 10−6 (±0.08)0.247 ± 0.001
BPA4.871 × 10−5 (±0.03)0.103 ± 0.0023.862 × 10−3 (±0.04)0.514 ± 0.001
a B16 melanoma and CT26 colon carcinoma cancer cells (5 × 103 cells) were incubated for 72 h in the presence of compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3, and then the percentages of viable cells were determined by MTT assay. The drug concentrations required to inhibit cell viability by 50% (IC50) were determined from semi-logarithmic concentration–response plots, and the results represent the means ± s.d. of triplicate samples. b B16 and CT26 cells (5 × 105 cells) were incubated for 3 h in the presence of compounds 2, 3, Ph3C2BCr2, and Ph3C2BCr3 or BPA (10.8 ppm). After washing three times, the accumulated boron concentrations were determined by inductively coupled plasma optical emission spectroscopy (ICP-OES). The values shown are the means ± s.d. from three samples.
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Ha, T.-J.; Im, D.-K.; Kim, S.-M.; Lee, J.-D. 1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations. Molecules 2023, 28, 4942. https://doi.org/10.3390/molecules28134942

AMA Style

Ha T-J, Im D-K, Kim S-M, Lee J-D. 1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations. Molecules. 2023; 28(13):4942. https://doi.org/10.3390/molecules28134942

Chicago/Turabian Style

Ha, Tae-Jin, Dong-Kyung Im, Seung-Min Kim, and Jong-Dae Lee. 2023. "1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations" Molecules 28, no. 13: 4942. https://doi.org/10.3390/molecules28134942

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