Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases

Zakšauskas, Audrius; Čapkauskaitė, Edita; Jezepčikas, Linas; Linkuvienė, Vaida; Kišonaitė, Miglė; Smirnov, Alexander; Manakova, E.; Gražulis, S.; Matulis, Daumantas

doi:10.1016/j.ejmech.2018.06.059

Cited by 11 publications

(9 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The appropriate 2,4-dichloro-5-sulfamoylbenzoic acid or 2,4-dibromo-5-sulfamoylbenzoic acid [ 8 ] (10.0 mmol) was refluxed in MeOH (100 mL) with concentrated H 2 SO 4 (1 mL) for 20 h. The reaction mixture was concentrated under reduced pressure.…”

Section: Methodsmentioning

confidence: 99%

“…The mixture of methyl 2,4-dichloro-5-sulfamoylbenzamide ( 11 ) [ 8 ] (269 mg, 1.00 mmol), DMSO (1.5 mL), appropriate thiol(1.10 mmol), and TEA (121 mg, 1.20 mmol) was heated at 60 °C temperature for 12 h. The mixture was cooled to room temperature, and brine (15 mL) was added. The product was extracted with EtOAc (3 × 15 mL).…”

Section: Methodsmentioning

confidence: 99%

“…Many CA inhibitors have been synthesized bearing flexible tails capable of finding an energetically favorable position in several CA isozymes, thus losing selectivity [ 6 , 7 ]. We have attempted to design inhibitors with a restrained position of the ring and two functional groups attached to the benzenesulfonamide [ 8 , 9 , 10 ]. This approach helped design inhibitors selective for CAVII, CAIX, CAXII, and CAXIV.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Zakšauskas

Čapkauskaitė

Paketurytė-Latvė

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Zakšauskas

Čapkauskaitė

Paketurytė-Latvė

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pK a of the zinc-bound water molecule at 25°C is 7.0-7.1. [33,34] A large body of work has resulted in the deposition of structural data for 24 crystal structures of chlorinated/ fluorinated mono-/di-substituted benzenesulfonamides bound to CA XII complexes [35][36][37][38][39][40][41][42] to the PDB. This forms a valuable resource for CA XII inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

“…). Drugs acetazolamide(35) and methazolamide(36) were nanomolar inhibitors of CA II (K d 46 and 100 nM) and bound up to 9-fold stronger than chCA XII or CA XII, while naphthalene-2-sulfonamide (37) similarly bound CA II stronger than chCA XII and CA XII (K d for CA II was 770 nM, while for chCA XII and CA XII -6700 and 6300 nM, respectively).…”

mentioning

confidence: 99%

Switching the Inhibitor‐Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII

et al. 2021

Self Cite

View full text Add to dashboard Cite

A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti‐cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure‐based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.

show abstract

Organic Synthesis of Substituted Chlorinated Benzenesulfonamides as Selective Inhibitors of Several CA Isoforms

Čapkauskaitė

Matulis

2019

Carbonic Anhydrase as Drug Target

View full text Add to dashboard Cite

Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases

Cited by 11 publications

References 62 publications

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Switching the Inhibitor‐Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII

Organic Synthesis of Substituted Chlorinated Benzenesulfonamides as Selective Inhibitors of Several CA Isoforms

Contact Info

Product

Resources

About