A new family of potential oncostatics: 2-chloroethylnitrososulfamides (CENS)—I. Synthesis, structure, and pharmacological evaluation (preliminary results)

doi:10.1016/0968-0896(96)00118-6

Bioorganic & Medicinal Chemistry

Volume 4, Issue 8, August 1996, Pages 1227-1235

https://doi.org/10.1016/0968-0896(96)00118-6 Get rights and content

Abstract

A new series of alkylating agents, 2-chloroethylnitrososulfamides (CENS), were developed on the model of 2-chloroethylnitrosoureas. Starting from chlorosulfonyl isocyanate, a four-step synthesis (carbamoylation-sulfamoylation, Mitsunobu alkylation, deprotection, and nitrosation) gives the title compounds in a 47–58% overall yield. The selection of the nitrosation site can be directed through an alternative route. The pharmacological evaluation shows a significant oncostatic activity towards both A549 and MCF7 cell lines.

A new series of alkylating agents, 2-chloroethylnitrososulfamides (CENS), were developed on the model of 2-chloroethylnitrosoureas. Starting from chlorosulfonyl isocyanate, a four-step synthesis (carbamoylation-sulfamoylation, Mitsunobu alkylation, deprotection and nitrosation) gives the title compounds. The pharmacological evaluation shows a significant oncostatic activity.

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The subsequent nitrosation reaction was carried out with sodium nitrite, which is not regiospecific and gives the N’-aryl-N-nitrosoureas as major and the N’-aryl-N’-nitrosoureas as a minor product (Fig. S2) as revealed by thin layer chromatography. Separation of the two isomers by column chromatography on silica gel was, however, straightforward and the structure of the CENUs was confirmed by 1H NMR spectroscopy and ESI-MS. In ESI-MS, all CENUs gave [M−NO + H]+ ion peaks corresponding to the loss of NO due to the instability of the N-nitroso group under ESI-MS conditions [27]. In 1H NMR, successful nitrosation was confirmed by disappearance of the exchangeable N-H protons and by appearance of an A2X2 system with a triplet between 3.10 and 3.75 ppm corresponding to the chloromethylene group and a triplet between 3.65 and 4.32 ppm corresponding to the CH2NNO group.
In view of the anticancer effect of nitrosoureas a set of four new N-(2-chloroethyl)-N-nitrosourea (CENU) derivatives was synthesized. An in silico absorption, distribution, metabolism, excretion and toxicity (ADME/Tox) prediction study revealed that the CENU derivatives satisfied all the required criteria for oral administration and introduced them as remarkable anticancer candidates in the central nervous system (CNS). A comparative solvatochromic study including the Kamlet-Taft, Catalán and Laurence models indicated that the solvatochromic behavior of the CENUs depended on both, unspecific and specific solvent–solute interactions. In detail, the solvatochromic effect of the solvent polarity on the absorption and emission maxima was significant for all CENUs, whereas the solvatochromic effect of the solvent’s ability to donate or accept hydrogen bonds on the absorption and emission maxima was critically dependent on the electron density of the N’-aryl group. From the solvatochromic comparison method, excellent correlations (r ≥ 0.890) were obtained between the ADME parameters and the solvatochromic regression coefficients obtained by the Catalán model. As potential stabilizers, inclusion complexes of the investigated CENU derivatives with β-cyclodextrin (β-CD) were also explored. The spectrofluorimetric host–guest experiments included double-reciprocal Benesi-Hildebrand plots as well as the molar ratio and continuous variation plots (Job’s plots), which established a 1:1 β-CD to CENU binding stoichiometry and relatively high affinities of β-CD for CENU derivatives.
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Recent drug recalls (e.g., valsartan and ranitidine) linked to the discovery of nitrosamine impurities have led to increased regulatory scrutiny in the manufacturing process of marketed medicines, notably for determining any sources of risk for nitrosamine (or related N-nitroso compound) formation within the manufacturing process. This review seeks to aid the risk assessment process through identifying known conditions and reactants through which N-nitroso compounds can be formed.
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Finally, for better understanding of biological molecule behavior before and after complexation, a detailed analysis of structure–chemical reactivity of the interesting drug, in free and in complexed state was undertaken at the end of this work. N-(2-chloroethyl), N-nitroso, N′, N′-dicyclohexylsulfamid derived from di-cyclohexylamin (DCY/CENS) molecule has been synthesized following the procedure described in Ref. [15]. The used chemicals are of high purity (analytical grade).
In this work, the inclusion complex of DCY/CENS: N-(2-chloroethyl), N-nitroso, N′, N′-dicyclohexylsulfamid and β-cyclodextrin (β-CD) is investigated using the fluorescence spectroscopy, PM3, ONIOM2 and DFT methods. The experimental part reveals that DCY/CENS forms a 1:1 stoichiometric ratio inclusion complex with β-CD. The constant of stability is evaluated using the Benesi-Hildebrand equation. The results of the theoretical optimization showed that the lipophilic fraction of molecule (cyclohexyl group) is inside of β-CD. Accordingly, the Nitroso-Chloroethyl moiety is situated outside the cavity of the macromolecule host. The favorable structure of the optimized complex indicates the existence of weak intermolecular hydrogen bonds and the most important van der Waals (vdW) interactions which are studied on the basis of Natural Bonding Orbital (NBO) analysis. The NBO is employed to compute the electronic donor–acceptor exchanges between drug and β-CD. Furthermore, a detailed topological charge density analysis based on the quantum theory of atoms in molecules (QTAIM), has been accomplished on the most favorable complex using B3LYP/6-31G(d) method. The presence of stabilizing intermolecular hydrogen bonds and van der Waals interactions in the most favorable complex is predicted. Also, the energies of these interactions are estimated with Espinosa's formula. The findings of this investigation reveal that the correlation between the structural parameters and the electronic density is good. Finally, and based on DFT calculations, the reactivity of the interesting molecule in free state was studied and compared with that in the complexed state using chemical potential, global hardness, global softness, electronegativity, electrophilicity and local reactivity descriptors.
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Bidistilled water was used in all of the experiments. The investigated compound was synthesised according to the procedure described in the literature [12]. All chemicals used were of high purity (analytical grade).
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^†: Permanent address: Department of Chemistry, University of Annaba, BP 12, El Hadjar, Algeria.

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A new family of potential oncostatics: 2-chloroethylnitrososulfamides (CENS)—I. Synthesis, structure, and pharmacological evaluation (preliminary results)

Abstract

Bioorg. Med. Chem.

Tetrahedron Lett.

J. Med. Chem.

Chemotherapy of Cancer

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Pure Appl. Chem.

J. Org. Chem.

Rec. Trav. Chim. Pays-Bas

Org. Synth. Coll.

J. Org. Chem.

Sulfamic Acid and its N-substituted Derivatives

J. Chem. Rev.

Angew. Chem. Int. Ed. Engl.