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. 2019 Jul 11;10(8):1205–1210. doi: 10.1021/acsmedchemlett.9b00252

Bis-benzoxaboroles: Design, Synthesis, and Biological Evaluation as Carbonic Anhydrase Inhibitors

Adèle Larcher †,‡, Alessio Nocentini §, Claudiu T Supuran §, Jean-Yves Winum ‡, Arie van der Lee ∥, Jean-Jacques Vasseur ‡, Danielle Laurencin †,*, Michael Smietana ‡,*
PMCID: PMC6691558  PMID: 31413806

Abstract

graphic file with name ml-2019-00252e_0004.jpg

The synthesis, characterization, and biological evaluation of a series of compounds incorporating two or three benzoxaborole moieties is reported. Three different synthetic strategies were used to explore within this series as much chemical space as possible, all starting from the 6-aminobenzoxaborole reagent: amide coupling, imine bond formation, and squarate coupling. Eleven new compounds were isolated in pure form, and single crystals were obtained for two of them. These compounds were then evaluated as carbonic anhydrase inhibitors against the cytosolic hCA I and II and the transmembrane hCA IV, IX, and XII isoforms. While the benzoxaborole scaffold has been recently introduced as a new chemotype for carbonic anhydrase inhibition, these new multivalent derivatives exhibited superior inhibitory activity against the tumor-associated isoform hCA IX. In particular, compared to monovalent 6-aminobenzoxaborole (KI = 813 nM) and 6-carboxybenzoxaborole (KI = 400 nM), derivative 2h characterized by a glutamic acid structural core and two benzoxaborole moieties was found to be more potent (KI = 64 nM) and more selective over human hCA II.

Keywords: Benzoxaborole, carbonic anhydrase, multivalency, enzyme inhibition

Boron-containing molecules are emerging as promising new drug candidates, targeting a wide range of diseases. Indeed, thanks to its vacant p orbital, boron is electrophilic and can reversibly interact with a large variety of nucleophiles, which results in a change of the hybridization state from sp2 to sp3. These unique physicochemical properties allow organoboron compounds to coordinate oxygen- and nitrogen-based ligands present in biomolecules making them ideal candidates for the development of new protein inhibitors.1,2 Interestingly, while approximately 280 mineral species containing boron are identified,3 natural products containing carbon–boron bonds are unknown and can only be obtained from organic synthesis or engineered enzymes.4 Moreover, the low toxicity of boron-based compounds (boric acid being the principal metabolite) reinforced the great attention given to this class of derivatives in drug development and led to the discovery and approval in 2003 of bortezomib, a dipeptide boronic acid for the treatment of multiple myeloma.5,6 More recently, vaborbactam, a cyclic boronic acid β-lactamase inhibitor, joined the family of approved boron-containing drug in combination with Meropenem for complicated urinary tract infections, including pyelonephritis.7,8 Among the various classes of boron-based candidates, benzoxaboroles have also emerged as a highly interesting class of heterocycles possessing remarkable antifungal, antibacterial, antiparasitic, anti-inflammatory, antiviral, and anticancer activities.9−11 Indeed, the presence of the organoboron function within the five-membered ring increases the electrophilic character of the boron, which more readily switches to a tetrahedral configuration in the presence of a nucleophile.

Tavaborole (AN2690) was the first benzoxaborole approved by FDA in July 2014 for the treatment of onychomycosis of the toenails, followed by Crisaborole (AN2728) in December 2016 for the treatment of mild-to-moderate atopic dermatitis (Figure 1). Several other biologically active benzoxaboroles are currently under clinical trials,12 all of them exploiting the unique physicochemical properties of this scaffold, which combines a high solubility in physiological media and target affinity with a strong Lewis acidity, as well as the ability to adopt an anionic tetrahedral configuration in the presence of biomolecules.13−16

Figure 1.

Figure 1

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Organoboron marketed drugs.

Recently, members of the benzoxaborole family have also been found to inhibit efficiently carbonic anhydrases (CA), thus expanding the biological activities of this class of compounds.17−19 While multivalent sulfonamide-based CA inhibitors have already demonstrated enhanced potencies,20−24 the exploration of bis- or multivalent benzoxaboroles has never been evaluated. Multivalent binding represents an attractive approach to enhance the binding affinity and potency of enzymes inhibitors.25,26 In this context, we recently reported a multinuclear (1H, 11B, 19F) NMR spectroscopy method to investigate the equilibria between small bis-benzoxaboroles and bisboronic acids with representative cis-diols derivatives.27 However, bis- or multibenzoxaborole architectures are currently limited to a handful of compounds.10,28−31,33,34 Here, we report the straightforward synthesis of a new series of bis- and tris-benzoxaboroles, and their evaluation as potential inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1).

The syntheses of the target compounds started with 6-aminobenzoxaborole 1, which was obtained in two steps from commercially available 1,3-dihydro-1-hydroxy-2,1-benzoxaborole following published procedures.17,35,36 Compound 1 was then connected to a series of bis- or tris-carboxylic acids by an amide coupling reaction with 2 equiv of hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and diisopropylethylamine (DIEA) in DMF. These reactions gave the corresponding bis- or tris-benzoxaboroles 2a–i in usually good yields with satisfactory NMR purity, most compounds being isolated by routine precipitation in water or methanol, after partial evaporation of DMF (Scheme 1).

Scheme 1. Synthesis of Bis- or Tris-benzoxaborole Derivatives.

Scheme 1

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Alternatively, 2 equiv of 1 were reacted with 2,5-thiophenedicarboxaldehyde in methanol to generate the diiminobenzoxaborole 3 in 95% yield. Compound 3 was, however, poorly soluble in organic media, and its reduction into the corresponding diamino derivative was troublesome (Scheme 1). Finally, to broaden the molecular diversity of the bis-benzoxaborole scaffold, 1 was coupled to dimethyl squarate to give squaramide 4 in 85% yield. This synthetic route was found to be very easy to achieve, leading to a bis-benzoxaborole compound with significant solubility in different solvents.

Crystal structures of 3 and 4 were obtained by recrystallization from DMSO (Figure 2). A significantly different arrangement of the molecules in the solid state was observed. Indeed, the benzoxaborole rings in the squarate derivative adopt a nearly coplanar configuration, while, for the thiophene derivative, the dihedral angle between the benzoxaborole aromatic planes is ∼32°. Interestingly, in contrast to many benzoxaborole crystal structures in which the organoboron units face each other forming H-bonds,37 no such interaction was observed here, due to the presence of DMSO in the crystal lattices of 3 and 4, which plays the role of hydrogen-bond acceptor for the B–O–H units in both cases.

Figure 2.

Figure 2

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Representation of the crystal structure arrangements in compounds (a) 3 and (b) 4. Full crystallographic details can be found in the Supporting Information.

Taken together, the synthetic approaches proposed here for the elaboration of 2a–I, 3, and 4 significantly contribute to expanding the range of bis-benzoxaboroles available because so far very few compounds of this sort had been described.28,30,32−34,38 While a much larger range of bis-benzoxaboroles can potentially be prepared along these new strategies, this first series of compounds was chosen as a means to probe the influence of the length and flexibility of the linkers connecting the benzoxaborole units (2a–f) in biological assays, as well as the importance of the spatial orientation of these moieties (2i, 3, and 4). Moreover, the substitution pattern of the linker was probed with the use of N-Boc-aspartic and N-Cbz-glutamic amino acids (2g and 2h).

Carbonic anhydrases (CAs) are ubiquitous zinc-containing metalloenzymes which catalyze the reversible conversion of water and carbon dioxide into bicarbonate with release of a proton.39,40 Twelve different catalytically active CA isoforms have been identified so far in humans (h), all belonging to the α-class and involved in various physiological roles including pH regulation, transport of CO2, gluconeogenesis, ureagenesis, or lipogenesis.41,42 While most hCAs are monomeric, homodimeric forms have also been reported.41 Considering the central role of hCAs in several biosynthetic reactions, these enzymes have been extensively studied as valuable targets for a wide range of pharmacological applications ranging from glaucoma (hCA II, hCA IV, and hCA XII) to cancer (hCA IV, hCA IX, and hCA XII). Carbonic anhydrases are important in many physiological processes in both normal and pathological states. Considering their critical role in cell homeostasis and the ubiquitous expression of some isoforms (such as hCA I and hCA II), inhibition of many hCA isoforms at the same time may lead to detrimental side effects. Inhibition of specific CA isoforms has been exploited for many years in the therapy of different pathologies. While hCA II, hCA IV, and hCA XII are usually referred as antiglaucoma drug targets, hCA IX and hCA XII are well-known tumor-associated isoforms and have been validated as antitumor/antimetastatic drug targets and may be used for imaging hypoxic tumors. Increasing isoform selectivity will consequently increase treatment effectiveness and reduce cytotoxicity (offtarget effects hCA I and hCA II) in patients.43−47 While ubiquitous hCA I and hCA II are generally considered as off-target, this novel series of compounds incorporating two or three benzoxaboroles moieties were evaluated by a stop-flow CO2 hydrase assay48 for their ability to inhibit cytosolic hCA I and hCA II, as well as the transmembrane tumor-associated hCA IV, IX, and XII. Acetazolamide (AAZ), a nonselective CA inhibitor was used as control. Additionally, monovalent 6-aminobenzoxaborole 1 and 6-carboxybenzoxaborole 5(49) were evaluated as well for comparison purposes (Table 1). Taken together, these data show that there is a significant influence of the nature of the linker between the benzoxaborole units on the hCA inhibition properties of these molecules, as the inhibition constants span over several orders of magnitude. Nevertheless, all of the newly synthesized compounds are weak inhibitors of the ubiquitous isoform hCA I, with only three compounds displaying inhibition constants in the submicromolar range (KI = 886, 813, and 850 nM for 2a, 2g, and 5 respectively). hCA II inhibition appeared to be slightly more efficient with seven compounds displaying KIs in the submicromolar range, compound 5 standing out here again as the most potent inhibitor (KI = 173 nM) and thus indicating that an additional benzoxaborole moiety in 2, 3, and 4 does not induce a significant impact on the activity toward these cytosolic CA isoforms.

Table 1. Inhibition Data of Human Isoforms hCA I, II, IV, IX, and XII with Compounds 1–5 and Standard Sulfonamide Inhibitor Acetazolamide (AAZ) by a Stopped Flow CO2 Hydrase Assay.

  KI (nM)a
 selectivity ratiob
cmpd hCA I hCA II hCA IV hCA IX hCA XII II/IV II/IX II/XII
1c 9334 ± 621 590 ± 46   813 ± 75 640 ± 55   0.73 0.92
2a 886 ± 57 339 ± 24 6276 ± 345 158 ± 13 125 ± 10 0.05 2.15 2.71
2b 2894 ± 157 342 ± 19 5239 ± 336 680 ± 45 404 ± 30 0.07 0.50 0.85
2c 3212 ± 234 1714 ± 125 19.8 × 103 ± 600 1480 ± 88 2982 ± 168 0.09 1.16 0.57
2d 1667 ± 98 541 ± 42 3444 ± 259 312 ± 24 82.0 ± 6.1 0.16 1.73 6.60
2e 2446 ± 152 2581 ± 158 12.2 × 103 ± 900 1120 ± 96 811 ± 59 0.21 2.30 3.18
2f 3297 ± 256 3930 ± 224 58.3 × 103 ± 4100 4872 ± 378 1623 ± 112 0.07 0.81 2.42
2g 813 ± 49 908 ± 58 35.6 × 103 ± 1500 280 ± 15 660 ± 39 0.03 3.23 1.38
2h 1778 ± 114 289 ± 16 16.2 × 103 ± 300 64.3 ± 4.4 89.6 ± 5.3 0.02 4.52 3.25
2i 21.9 × 103 ± 1500 39.3 × 103 ± 2400 >100 × 103 8629 ± 568 528 ± 45   4.55 74.41
3 4133 ± 365 2344 ± 156 29.7× 103 ± 2000 203 ± 19 181 ± 16 0.08 11.55 12.88
4 3075 ± 247 2275 ± 148 25.6 × 103 ± 1800 2967 ± 201 822 ± 65 0.09 0.77 2.77
5 850 ± 59 173 ± 14 1420 ± 89 400 ± 35 59.0 ± 4.7 0.12 0.44 2.95
AAZ 250 ± 18 12 ± 1 75.4 ± 4.2 25 ± 1 2.5 ± 0.1 0.16 0.48 4.80
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a

Mean from three different assays, by a stopped flow technique.

b

Selectivity as determined by the ratio of KIs for isozymes hCA II relative to hCA IV, IX, and XII.

c

Values from ref (15).

The membrane-bound hCA IV was the least inhibited isoform of this study with KIs always >1000 nM. Interestingly, the transmembrane isoform hCA IX was more efficiently inhibited with KIs ranging between 64 and 8629 nM. Amino acid derivative 2h induced the best inhibition profile against this tumor-associated isoform (KI = 64 nM) and a selectivity ratio of 4.55 against hCA II, while 3 gave the best selectivity ratio (KIs hCA II/hCA IV = 11.55) but was less potent (KI = 203 nM). Compound 2h was also among the most potent inhibitors of the tumor-associated isoform hCA XII (KI = 89 nM), along with derivatives 2d (KI = 82 nM) and 5 (KI = 59 nM). In this series the highest selectivity ratio was achieved by 2i, which is substituted by three benzoxaborole units (KIs hCA II/hCA XII = 74.41). While a clear structure–activity correlation is difficult to achieve, it appears that 6-carboxybenzoxaborole 5 was more potent than its 6-aminobenzoxaborole 1 analog. In the case of divalent derivatives, the presence of a saturated linker between the benzoxaboroles units induces higher inhibition constants and selectivities than their unsaturated analogues, although the observed KIs cannot be correlated with the number of carbon atoms. Similarly, increasing the number of unsaturation seems to decrease the inhibition of hCA IX and hCA XII. However, it is worth stressing that amino acid derivative 2h stood out as the best candidate notably against hCA IX. Unfortunately, any attempt to remove its Cbz protecting group to evaluate the influence of the free amino group led to degradation of the product. Nevertheless, these results suggest a positive effect of the glutamic central core compared to its aspartic analogue against hCA IX and hCA XII. Contrastingly, the number of benzoxaborole moieties do not seem to induce multivalent effects on hCA inhibition as suggested by the inhibition observed with derivative 2i. Similarly, the spatial orientation of the benzoxaborole moieties offered by 3 and 4 did not translate in effective hCA inhibition, but it is interesting to note that 3 led generally to good selectivity ratio over hCA II.

Although 6-carboxybenzoxaborole 5 was more potent than its 6-aminobenzoxaborole 1 analogue, we envisioned from the start that a higher chemical diversity could be obtained with the amino function compared to the carboxylic acid group. This is mainly demonstrated with derivatives 2g, 3, and 4 and more particularly with 2h that could not have been obtained from 6-carboxybenzoxaborole and leads to promising inhibitory activity and selectivity.

In conclusion, we reported here the synthesis and characterization of a set of ten novel bis-benzoxaboroles and one tris-benzoxaborole, all obtained in one step from readily available 6-aminobenzoxaborole. These novel compounds were investigated as inhibitors of five carbonic anhydrases isoforms involved in severe pathologies comprising glaucoma, epilepsy, and cancer. These carbonic anhydrases were generally inhibited in the micromolar range by the reported compound. Among this series, 2h composed of a glutamic acid central core and two benzoxaborole moieties showed potent inhibition against the tumor-associated isoform hCA IX (KI = 64 nM). Compared to monovalent 6-aminobenzoxaborole (KI = 813 nM) and 6-carboxybenzoxaborole (KI = 400 nM), the structure of 2h highlights the importance of the substitution pattern of the linker connecting the benzoxaboroles moieties and supports the development of amino acid-based benzoxaboroles inhibitors. Moreover, these results confirm the growing importance of benzoxaboroles as CA inhibitors and more generally of organoboron compounds in drug discovery. Beyond the biological assays, the easy access to these multibenzoxaborole molecules appears as highly attractive for the elaboration of novel supramolecular entities based on benzoxaborole/diol interactions, and this is a point we are currently looking into.

Acknowledgments

D. Granier is acknowledged for recording the single crystal X-ray diffraction data.

Glossary

ABBREVIATIONS

hCA

human carbonic anhydrase

CAI

carbonic anhydrase inhibitor

KI

inhibition constant

HATU

hexafluorophosphate azabenzotriazole tetramethyl uronium

DIEA

diisopropylethylamine

AAZ

acetazolamide

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.9b00252.

  • Characterization data and Experimental details and of all compounds reported (PDF)

  • Full crystallography details of compounds 3 (CCDC 1912796) (PDF) and 4 (CCDC 1912797) (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This work has benefited from funding by the French National Research Agency (ANR) under the program “Investissement d’avenir”, LabEx CheMISyst (grant number ANR-10-LabX 05-01).

The authors declare no competing financial interest.

Supplementary Material

ml9b00252_si_001.pdf (2.8MB, pdf)
ml9b00252_si_002.pdf (107.2KB, pdf)
ml9b00252_si_003.pdf (110.3KB, pdf)

References

  1. Ban H. S.; Nakamura H. Boron-based drug design. Chem. Rec. 2015, 15, 616–635. 10.1002/tcr.201402100. [DOI] [PubMed] [Google Scholar]
  2. Diaz D. B.; Yudin A. K. The versatility of boron in biological target engagement. Nat. Chem. 2017, 9, 731–742. 10.1038/nchem.2814. [DOI] [PubMed] [Google Scholar]
  3. Grew E. S. Boron - The crustal element. Elements 2015, 11, 162–163. [Google Scholar]
  4. Kan S. B. J.; Huang X.; Gumulya Y.; Chen K.; Arnold F. H. Genetically programmed chiral organoborane synthesis. Nature 2017, 552, 132. 10.1038/nature24996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Richardson P. G.; Barlogie B.; Berenson J.; Singhal S.; Jagannath S.; Irwin D.; Rajkumar S. V.; Srkalovic G.; Alsina M.; Alexanian R.; Siegel D.; Orlowski R. Z.; Kuter D.; Limentani S. A.; Lee S.; Hideshima T.; Esseltine D. L.; Kauffman M.; Adams J.; Schenkein D. P.; Anderson K. C. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 2003, 348, 2609–2617. 10.1056/NEJMoa030288. [DOI] [PubMed] [Google Scholar]
  6. Adams J.; Behnke M.; Chen S. W.; Cruickshank A. A.; Dick L. R.; Grenier L.; Klunder J. M.; Ma Y. T.; Plamondon L.; Stein R. L. Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids. Bioorg. Med. Chem. Lett. 1998, 8, 333–338. 10.1016/S0960-894X(98)00029-8. [DOI] [PubMed] [Google Scholar]
  7. Hecker S. J.; Reddy K. R.; Totrov M.; Hirst G. C.; Lomovskaya O.; Griffith D. C.; King P.; Tsivkovski R.; Sun D.; Sabet M.; Tarazi Z.; Clifton M. C.; Atkins K.; Raymond A.; Potts K. T.; Abendroth J.; Boyer S. H.; Loutit J. S.; Morgan E. E.; Durso S.; Dudley M. N. Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases. J. Med. Chem. 2015, 58, 3682–3692. 10.1021/acs.jmedchem.5b00127. [DOI] [PubMed] [Google Scholar]
  8. Lomovskaya O.; Sun D.; Rubio-Aparicio D.; Nelson K.; Tsivkovski R.; Griffith D. C.; Dudley M. N. Vaborbactam: Spectrum of β-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae. Antimicrob. Agents Chemother. 2017, 61, e01443. 10.1128/AAC.01443-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Liu C. T.; Tomsho J. W.; Benkovic S. J. The unique chemistry of benzoxaboroles: current and emerging applications in biotechnology and therapeutic treatments. Bioorg. Med. Chem. 2014, 22, 4462–4473. 10.1016/j.bmc.2014.04.065. [DOI] [PubMed] [Google Scholar]
  10. Adamczyk-Woźniak A.; Borys K. M.; Sporzyński A. Recent developments in the chemistry and biological applications of benzoxaboroles. Chem. Rev. 2015, 115, 5224–5247. 10.1021/cr500642d. [DOI] [PubMed] [Google Scholar]
  11. Mereddy G. R.; Chakradhar A.; Rutkoski R. M.; Jonnalagadda S. C. Benzoboroxoles: synthesis and applications in medicinal chemistry. J. Organomet. Chem. 2018, 865, 12–22. 10.1016/j.jorganchem.2018.03.017. [DOI] [Google Scholar]
  12. Nocentini A.; Supuran C. T.; Winum J. Y. Benzoxaborole compounds for therapeutic uses: a patent review (2010–2018). Expert Opin. Ther. Pat. 2018, 28, 493–504. 10.1080/13543776.2018.1473379. [DOI] [PubMed] [Google Scholar]
  13. Palencia A.; Liu R. J.; Lukarska M.; Gut J.; Bougdour A.; Touquet B.; Wang E. D.; Li X. F.; Alley M. R. K.; Freund Y. R.; Rosenthal P. J.; Hakimi M. A.; Cusack S. Cryptosporidium and toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 2016, 60, 5817–5827. 10.1128/AAC.00873-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sonoiki E.; Palencia A.; Guo D. H.; Ahyong V.; Dong C.; Li X. F.; Hernandez V. S.; Zhang Y. K.; Choi W.; Gut J.; Legac J.; Cooper R.; Alley M. R. K.; Freund Y. R.; DeRisi J.; Cusack S.; Rosenthal P. J. Antimalarial benzoxaboroles target plasmodium falciparum leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 2016, 60, 4886–4895. 10.1128/AAC.00820-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Tomsho J. W.; Pal A.; Hall D. G.; Benkovic S. J. Ring structure and aromatic substituent effects on the pKa of the benzoxaborole pharmacophore. ACS Med. Chem. Lett. 2012, 3, 48–52. 10.1021/ml200215j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dowlut M.; Hall D. G. An improved class of sugar-binding boronic acids, soluble and capable of complexing glycosides in neutral water. J. Am. Chem. Soc. 2006, 128, 4226–4227. 10.1021/ja057798c. [DOI] [PubMed] [Google Scholar]
  17. Alterio V.; Cadoni R.; Esposito D.; Vullo D.; Di Fiore A.; Monti S. M.; Caporale A.; Ruvo M.; Sechi M.; Dumy P.; Supuran C. T.; De Simone G.; Winum J. Y. Benzoxaborole as a new chemotype for carbonic anhydrase inhibition. Chem. Commun. 2016, 52, 11983–11986. 10.1039/C6CC06399C. [DOI] [PubMed] [Google Scholar]
  18. Nocentini A.; Cadoni R.; del Prete S.; Capasso C.; Dumy P.; Gratteri P.; Supuran C. T.; Winum J. Y. Benzoxaboroles as efficient inhibitors of the beta-carbonic anhydrases from pathogenic fungi: activity and modeling study. ACS Med. Chem. Lett. 2017, 8, 1194–1198. 10.1021/acsmedchemlett.7b00369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nocentini A.; Cadoni R.; Dumy P.; Supuran C. T.; Winum J. Y. Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles. J. Enzyme Inhib. Med. Chem. 2018, 33, 286–289. 10.1080/14756366.2017.1414808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kanfar N.; Tanc M.; Dumy P.; Supuran C. T.; Ulrich S.; Winum J. Y. Effective access to multivalent inhibitors of carbonic anhydrases promoted by peptide bioconjugation. Chem. - Eur. J. 2017, 23, 6788–6794. 10.1002/chem.201700241. [DOI] [PubMed] [Google Scholar]
  21. Casini A.; Abbate F.; Scozzafava A.; Supuran C. T. Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with a bis-sulfonamide - Two heads are better than one?. Bioorg. Med. Chem. Lett. 2003, 13, 2759–2763. 10.1016/S0960-894X(03)00508-0. [DOI] [PubMed] [Google Scholar]
  22. Touisni N.; Kanfar N.; Ulrich S.; Dumy P.; Supuran C. T.; Mehdi A.; Winum J. Y. Fluorescent silica nanoparticles with multivalent inhibitory effects towards carbonic anhydrases. Chem. - Eur. J. 2015, 21, 10306–10309. 10.1002/chem.201501037. [DOI] [PubMed] [Google Scholar]
  23. Carta F.; Osman S. M.; Vullo D.; AlOthman Z.; Supuran C. T. Dendrimers incorporating benzenesulfonamide moieties strongly inhibit carbonic anhydrase isoforms I-XIV. Org. Biomol. Chem. 2015, 13, 6453–6457. 10.1039/C5OB00715A. [DOI] [PubMed] [Google Scholar]
  24. Carta F.; Osman S. M.; Vullo D.; Gullotto A.; Winum J. Y.; AlOthman Z.; Masini E.; Supuran C. T. Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action. J. Med. Chem. 2015, 58, 4039–4045. 10.1021/acs.jmedchem.5b00383. [DOI] [PubMed] [Google Scholar]
  25. Badjic J. D.; Nelson A.; Cantrill S. J.; Turnbull W. B.; Stoddart J. F. Multivalency and cooperativity in supramolecular chemistry. Acc. Chem. Res. 2005, 38, 723–732. 10.1021/ar040223k. [DOI] [PubMed] [Google Scholar]
  26. Mahon E.; Barboiu M. Synthetic multivalency for biological applications. Org. Biomol. Chem. 2015, 13, 10590–10599. 10.1039/C5OB01357G. [DOI] [PubMed] [Google Scholar]
  27. Larcher A.; Lebrun A.; Smietana M.; Laurencin D. A multinuclear NMR perspective on the complexation between bisboronic acids and bisbenzoxaboroles with cis-diols. New J. Chem. 2018, 42, 2815–2823. 10.1039/C7NJ04143H. [DOI] [Google Scholar]
  28. Adamczyk-Woźniak A.; Borys K. M.; Madura I. D.; Michałek S.; Pawełko A. Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles and their boronic acid analogs. Tetrahedron 2013, 69, 8936–8942. 10.1016/j.tet.2013.07.102. [DOI] [Google Scholar]
  29. Adamczyk-Woźniak A.; Ejsmont K.; Gierczyk B.; Kaczorowska E.; Matuszewska A.; Schroeder G.; Sporzyński A.; Zarychta B. Novel 2,6-disubstituted phenylboronic compounds – Synthesis, crystal structures, solution behaviour and reactivity. J. Organomet. Chem. 2015, 788, 36–41. 10.1016/j.jorganchem.2015.04.026. [DOI] [Google Scholar]
  30. Pal A.; Bérubé M.; Hall D. G. Design, Synthesis, and screening of a library of peptidyl bis(boroxoles) as oligosaccharide receptors in water: identification of a receptor for the tumor marker TF-antigen disaccharide. Angew. Chem., Int. Ed. 2010, 49, 1492–1495. 10.1002/anie.200906620. [DOI] [PubMed] [Google Scholar]
  31. Claes D.; Holzapfel M.; Clausen N.; Maison W. Synthesis of adamantane-based trimeric benzoboroxoles. Eur. J. Org. Chem. 2013, 2013, 6361–6371. 10.1002/ejoc.201300769. [DOI] [Google Scholar]
  32. Cairns J. F.; Snyder H. R. Derivatives of 1,4-xylene-2,5-diboronic acid + 1,4-xylene-2-boronic acid. J. Org. Chem. 1964, 29, 2810–2812. 10.1021/jo01032a536. [DOI] [Google Scholar]
  33. Wieczorek D.; Lipok J.; Borys K. M.; Adamczyk-Wozniak A.; Sporzynski A. Investigation of fungicidal activity of 3-piperazine-bis(benzoxaborole) and its boronic acid analogue. Appl. Organomet. Chem. 2014, 28, 347–350. 10.1002/aoc.3132. [DOI] [Google Scholar]
  34. Adamczyk-Wozniak A.; Komarovska-Porokhnyavets O.; Misterkiewicz B.; Novikov V. P.; Sporzynski A. Biological activity of selected boronic acids and their derivatives. Appl. Organomet. Chem. 2012, 26, 390–393. 10.1002/aoc.2880. [DOI] [Google Scholar]
  35. Lennarz W. J.; Snyder H. R. Arylboronic acids 0.4. Reaction of boronophtalide. J. Am. Chem. Soc. 1960, 82, 2172–2175. 10.1021/ja01494a021. [DOI] [Google Scholar]
  36. Fu Z. Y.; He J. P.; Tong A. P.; Xie Y. M.; Wei Y. Q. A Convenient and efficient synthesis of dipeptidyl benzoxaboroles and their peptidomimetics. Synthesis 2013, 45, 2843–2852. 10.1055/s-0033-1339550. [DOI] [Google Scholar]
  37. Sene S.; Berthomieu D.; Donnadieu B.; Richeter S.; Vezzani J.; Granier D.; Begu S.; Mutin H.; Gervais C.; Laurencin D. A combined experimental-computational study of benzoxaborole crystal structures. CrystEngComm 2014, 16, 4999–5011. 10.1039/c4ce00313f. [DOI] [Google Scholar]
  38. Cho I.; Meimetis L.; Britton R. Bidirectional Metalation of Hydrobenzoin: Direct access to new chiral ligands and auxiliaries. Org. Lett. 2009, 11, 1903–1906. 10.1021/ol900323u. [DOI] [PubMed] [Google Scholar]
  39. Supuran C. T. Carbonic anhydrases - an overview. Curr. Pharm. Des. 2008, 14, 603–614. 10.2174/138161208783877884. [DOI] [PubMed] [Google Scholar]
  40. Supuran C. T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discovery 2008, 7, 168–181. 10.1038/nrd2467. [DOI] [PubMed] [Google Scholar]
  41. Supuran C. T. Structure and function of carbonic anhydrases. Biochem. J. 2016, 473, 2023–2032. 10.1042/BCJ20160115. [DOI] [PubMed] [Google Scholar]
  42. Boone C. D.; Habibzadegan A.; Gill S.; McKenna R. Carbonic anhydrases and their biotechnological applications. Biomolecules 2013, 3, 553–562. 10.3390/biom3030553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Supuran C. T. Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opin. Invest. Drugs 2018, 27, 963–970. 10.1080/13543784.2018.1548608. [DOI] [PubMed] [Google Scholar]
  44. Supuran C. T. Applications of carbonic anhydrases inhibitors in renal and central nervous system diseases. Expert Opin. Ther. Pat. 2018, 28, 713–721. 10.1080/13543776.2018.1519023. [DOI] [PubMed] [Google Scholar]
  45. Supuran C. T.; Alterio V.; Di Fiore A.; D’ Ambrosio K.; Carta F.; Monti S. M.; De Simone G. Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one. Med. Res. Rev. 2018, 38, 1799–1836. 10.1002/med.21497. [DOI] [PubMed] [Google Scholar]
  46. Supuran C. T.; Winum J. Y. Carbonic anhydrase IX inhibitors in cancer therapy: an update. Future Med. Chem. 2015, 7, 1407–1414. 10.4155/fmc.15.71. [DOI] [PubMed] [Google Scholar]
  47. Alterio V.; Di Fiore A.; D’Ambrosio K.; Supuran C. T.; De Simone G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms?. Chem. Rev. 2012, 112, 4421–4468. 10.1021/cr200176r. [DOI] [PubMed] [Google Scholar]
  48. Khalifah R. G. Carbon dioxide hydration of carbonic anhydrase. 1. Stop-flow kinetic studies on native human isoenzyme-B and isoenzyme-C. J. Biol. Chem. 1971, 246, 2561. [PubMed] [Google Scholar]
  49. Li H.; Wang H.; Liu Y.; Liu Z. A benzoboroxole-functionalized monolithic column for the selective enrichment and separation of cis-diol containing biomolecules. Chem. Commun. 2012, 48, 4115–4117. 10.1039/c2cc30230f. [DOI] [PubMed] [Google Scholar]

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ml9b00252_si_001.pdf (2.8MB, pdf)
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ml9b00252_si_003.pdf (110.3KB, pdf)

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