Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX

Dvořanová, Jana; Kugler, Michaël; Holub, Josef; Šícha, Václav; Das, Viswanath; Nekvinda, Jan; Anwar, Suzan El; Havránek, M.; Pospíšilová, Klára; Fábry, Milan; Král, Vlastimil; Medvedíková, Martina; Matějková, Stanislava; Lišková, Barbora; Gurská, Soňa; Džubák, Petr; Brynda, J.; Hajdúch, Marián; Grüner, Bohumı́r; Řezáčová, P.

doi:10.1016/j.ejmech.2020.112460

Cited by 27 publications

(62 citation statements)

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“…The series of sulphonamido carboranes contained a sulphonamidoalkyl group attached to alternative clusters: 1,2-dicarba- closo -dodecaborane (here referred to as closo clusters) or 7,8-dicarba- nido -undecaborate(1-) (here referred to as nido clusters). Compounds containing an alkyl linker with a length of n = 1 to n = 4 (compounds 1a – 4a and 1 b − – 4b − ) were designed and synthetised in our previous work 35 . Synthesis of compounds with a longer linker length of n = 5 and n = 6 between the sulfonamide group and the carborane cluster (compounds 5a – 6a and 5 b − – 6b − ) was carried out using a procedure analogous to the one used for the carboranes with shorter linkers ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

“… a The selectivity index is the ratio between Ki (CA II) and Ki (CA IX). b K i values from Dvořanová et al., 2020 35 . c Structure reported in Dvořanová et al, 2020 35 ; N.D. not determined.…”

Section: Resultsmentioning

confidence: 99%

“… b K i values from Dvořanová et al., 2020 35 . c Structure reported in Dvořanová et al, 2020 35 ; N.D. not determined. …”

Section: Resultsmentioning

confidence: 99%

“…All other compounds were modelled in one conformation with full occupancy. *Crystal structures of 3a and 3 b − in complex with CA IX-mimic, published previously 35 , are shown for comparison. (B) Compound 3a was modelled in two alternative conformations with partial occupancies of 0.8 and 0.2.…”

Section: Resultsmentioning

confidence: 99%

“…In our recent study, we explored the inhibitory activity of sulfonamide dicarbaboranes containing 12-vertex closo or 11-vertex nido carborane clusters with carbon atoms in adjacent position 35 . Variation in inhibitory properties and selectivity towards the cancer-specific CA IX isoform depending on the length of the alkyl linker interconnecting sulfonamide moiety with the carborane cluster was observed.…”

Section: Introductionmentioning

confidence: 99%

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The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX

Kugler

Holub

Brynda

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“… b K i values from Dvořanová et al., 2020 35 . c Structure reported in Dvořanová et al, 2020 35 ; N.D. not determined. …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX

Kugler

Holub

Brynda

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

et al. 2021

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This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space‐filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure‐activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster‐containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster‐containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).

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Direct Introduction of an Alkylsulfonamido Group on C‐sites of Isomeric Dicarba‐closo‐dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer‐Associated Carbonic Anhydrase IX Isoenzyme

Nekvinda

Kugler

Holub

et al. 2020

Chemistry A European J

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Carbonic anhydrase IX (CA IX), at umor-associated metalloenzyme, represents avalidated target for cancertherapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closododecaboranes group(s) prepared using an ew direct fivestep synthesis from the correspondingp arent cages. The protocol offers ar eliable solutionf or synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with ad ifferent geometric positiono fc arbon atoms. The closo-compounds from the ortho-and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1À) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant(K i)a nd selectivity towardsC AI X. Decreasing trends in K i ands electivity index (S I)v alues are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography,a nd eight high-resolution crystal structures uncovered the structuralb asis of inhibition potencya nd selectivity.

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Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX

Cited by 27 publications

References 62 publications

The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX

The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

Direct Introduction of an Alkylsulfonamido Group on C‐sites of Isomeric Dicarba‐closo‐dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer‐Associated Carbonic Anhydrase IX Isoenzyme

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