Novel Re(I) tricarbonyl coordination compounds based on 2-pyridyl-1,2,3-triazole derivatives bearing a 4-amino-substituted benzenesulfonamide arm: synthesis, crystal structure, computational studies and inhibitory activity against carbonic anhydrase I, II, and IX isoforms†.

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.

Tricarbonylrhenium complexes from 2-pyridyl-1,2,3-triazole ligands bearing a 4-substituted phenyl arm: a combined experimental and theoretical study.

Three new pyridyltriazole ligands (named pyta) bearing a 4-substituted phenyl arm (nitro- (2a), chloro- (2b) or aminophenyl (2c) moiety) have been synthesized using a convenient click chemistry strategy. The corresponding tricarbonylrhenium complexes 3a, 3b and 3c were prepared and fully characterized by means of NMR, IR and mass spectrometry, as well as X-ray crystallography for two of them (3a and 3b). The direct connection of a 4-substituted phenyl arm at the N1 position of the triazolyl ring has a significant influence on the geometry of both, the ligands and their corresponding Re-complexes. The dominant structural feature of these complexes concerns the crystal cohesion. Slip-stacked π-π interactions between two molecules of the complex were observed for 3a and 3b probably resulting from the co-planarity of the organic framework. Furthermore, a combined experimental study and DFT calculations showed that the nature of the pendant arm (X = NO2, NH2 or Cl) could affect the electronic properties of the Re-complexes. If the chloro- or aminophenyl moieties unmodified the photo-physical properties of the complexes 3b and 3c, the presence of a nitrophenyl arm for the complex 3a quenched the luminescence, due to a high probability of non-radiative deactivation.

A spectrophotometric and thermodynamic study of the charge-transfer complexes of N-aryl-N'-isopropyloxycarbonylsulfamides with DDQ and TCNE.

Molecular charge-transfer complexes of three N-aryl-N'-isopropyloxycarbonylsulfamides derivatives with π-acceptors tetracyanoethylene (TCNE), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), were studied by using zero and second order derivative UV spectrophotometry in different solvents at four different temperatures within the range of 20-35 °C. The stoichiometries of the complexes were found to be 1:1 ratio between donors and acceptors using Job's method. The data were analyzed in terms of their stability constant (K), molar extinction coefficient (εCT), thermodynamic standard reaction quantities (ΔG°, ΔH°, ΔS°), oscillator strength (f), transition dipole moment (µEN) and ionization potential (ID). The results show that the stability constant (K) for the complexes was found to be dependant upon the nature of electron acceptor, electron donor, and polarity of used solvents.

tert-Butyl N-[N,N-bis-(2-chloro-ethyl)sulfamo-yl]-N-(2-chloro-ethyl)carbamate.

The title compound, C(11)H(21)Cl(3)N(2)O(4)S, was produced as part of a development programme of a new synthetic route to chloro-ethyl-nitro-sosulfamides (CENS) with three chloro-ethyl moieties. These compounds possess structural features that confer potential biological activity and act as alkyl-ating agents. The packing is governed by four weak C-H⋯O inter-actions, forming an infinite three-dimensional network.

Carbonic anhydrase inhibitors. N-cyanomethylsulfonamides--a new zinc binding group in the design of inhibitors targeting cytosolic and membrane-anchored isoforms.

A series of N-cyanomethyl aromatic sulfonamides and bis-sulfonamides was prepared by reaction of arylsulfonyl halides with aminoacetonitrile. The obtained derivatives incorporated various aryl moieties, such as 4-halogeno/alkyl/aryl/nitro-substituted-phenyl, pentafluorophenyl or 2-naphthyl. Moderate inhibitory activity was detected for some compounds against the cytosolic human isoform II of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA II, with inhibition constants of 90, 180 and 560n M for the 4-nitrophenyl-, 4-iodophenyl- and pentafluorophenyl-N-cyanomethylsulfonamides, respectively. Other derivatives acted as weak inhibitors of isoforms hCA I (KIs of 720 nM-45 microM), hCA II (KIs of 1000-9800 nM) and hCA IX (KIs of 900-10200 nM). Thus, the N-cyanomethylsulfonamide zinc binding group is less effective than the sulfonamide, sulfamate or sulfamide ones for the design of effective CA inhibitors.

Study on the decomposition of 2-chloroethylnitro- sosulfamides (CENS) in serum using HPLC on-line solid phase extraction.

In this paper we have investigated the kinetic decomposition of 2-chloroethylnitrososulfamides (CENS) in fetal calf serum. The study was monitored by on-line solid phase extraction linked to RP-LC-MS. We demonstrated that CENS are less stable in fetal calf serum than in aqueous buffer at pH 7.4 and 37 degrees C. Moreover, we have shown that partition coefficient of CENS can be correlated to the kinetics decomposition, and we observe that the stability is better for lipophilic CENS. The different metabolites after decomposition have been tentatively identified by RP-HPLC-MS. This study indicates the formation of several metabolites resulting from a mechanism of decomposition more complex than in aqueous phosphate buffer, nevertheless, leading to the same main products.

Kinetic investigation on aqueous decomposition of 2-chloroethylnitrososulfamide.

The kinetics decomposition of 2-chloroethylnitrososulfamides (CENS) was studied in aqueous buffered solutions with pH ranging from 0 to 14. The study was monitored by RP-LC-MS and conventional UV spectrophotometry. The reaction proceeded via a pseudo-first-order kinetic with significant correlation coefficient. The major decomposition products from CENS after incubation in phosphate buffer were isolated and identified by NMR and mass spectrometry. The results indicate that the mechanism pathway involves a denitrosation of the CENS and competitive hydrolysis with nucleophilic attack on the sulfur atom and formation of sulfamate compounds.