RESUMO
Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Tiocarbamatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/químicaRESUMO
The reaction of 2,2-dimethoxy-N-methylethyllamine or 2-methyl-1,3-dioxolane with CS(2) in alkaline media produced two novel dithiocarbamate salts. Subsequent reactions with organotin halides yielded six new complexes: [SnMe(2){S(2)CNR(R(1))(2)}(2)] (1), [Sn(n-Bu)(2){S(2)CNR(R(1))(2)}(2)] (2), [SnPh(2){S(2)CNR(R(1))(2)}(2)] (3), [SnMe(2){S(2)CNR(R(2))(2)}(2)] (4), [Sn(n-Bu)(2){S(2)CNR(R(2))(2)}(2)] (5), [SnPh(2){S(2)CNR(R(2))(2)}(2)] (6), where R = methyl, R(1) = CH(2)CH(OMe)(2), and R(2) = 2-methyl-1,3-dioxolane. All compounds were identified in terms of infrared, (1)H and (13)C NMR, and the complexes were also characterized using (119)Sn NMR, (119)Sn Mössbauer and X-ray crystallography. The biological activity of all derivatives has been screened in terms of IC(90) and IC(50) against Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus, Penicillium citrinum, Curvularia senegalensis, Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Streptococcus sanguinis, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, and Pseudomonas aeruginosa and the results correlated well with a performed study of structure-activity relationship (SAR). Complexes (3), (5) and (6) displayed the best IC(90) and IC(50) in the presence of the fungi, greater than that of miconazole, used as control drug.
Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Desenho de Fármacos , Fungos/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Tiocarbamatos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Bactérias/crescimento & desenvolvimento , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fungos/crescimento & desenvolvimento , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Compostos Orgânicos de Estanho/síntese química , Compostos Orgânicos de Estanho/química , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/químicaAssuntos
Antifúngicos/química , Compostos de Rutênio/química , Tiocarbamatos/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Fenômenos Químicos , Espectroscopia de Ressonância Magnética , Compostos de Rutênio/síntese química , Compostos de Rutênio/farmacologia , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologiaRESUMO
Per-O-tert-butyldimethylsilyl-α,ß-d-galactofuranosyl isothiocyanate (4) was synthesized by the reaction of per-O-TBS-ß-d-galactofuranose (1) with KSCN, promoted by TMSI. Upon O-desilylation (1,2-dideoxy-α-d-galactofuranoso)[1,2d]-1,3-oxazolidine-2-thione (6), the cis-fused bicyclic thiocarbamate was obtained as the only product. Conformational analysis, aided by molecular modelling, showed two stable twist forms ((3)T(4) and (4)T(O)) for the five-membered sugar ring in 6. In aqueous solution, the equilibrium favours the first conformation (3:1 ratio). On the other hand, this ratio decreases for less polar solvents.
Assuntos
Galactose/análogos & derivados , Isotiocianatos/química , Compostos de Organossilício/química , Oxazóis/química , Tiocarbamatos/química , Galactose/química , Modelos Moleculares , Conformação Molecular , Tiocarbamatos/síntese químicaRESUMO
Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Aporfinas/química , Aporfinas/síntese química , Peumus/química , Tiocarbamatos/química , Tiocarbamatos/síntese química , Aporfinas/isolamento & purificação , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Tiocarbamatos/isolamento & purificaçãoRESUMO
The dimethyl-, di-n-butyl-, and diphenyltin(IV) dithiocarbamate (dtc) complexes [{R2Sn(L-dtc)}x] 1-7 (1, L = L1, R = Me; 2, L = L1, R = n-Bu; 3, L = L2, R = Me, x = infinity; 4, L = L2, R = n-Bu; 5, L = L3, R = Me, x = 2; 6, L = L3, R = n-Bu, x = 2; 7, L = L3, R = Ph, x = 2) have been prepared from a series of secondary amino acid (AA) homologues as starting materials: N-benzylglycine (alpha-AA derivative = L1), N-benzyl-3-aminopropionic acid (beta-AA derivative = L2), and N-benzyl-4-aminobutyric acid (gamma-AA derivative = L3). The resulting compounds have been characterized by elemental analysis, mass spectrometry, IR and NMR ((1)H, (13)C, and (119)Sn) spectroscopy, thermogravimetric analysis, and X-ray crystallography, showing that in all complexes both functional groups of the heteroleptic ligands are coordinated to the tin atoms. By X-ray diffraction analysis, it could be shown that [{Me2Sn(L2-dtc)}x] (3) is polymeric in the solid state, while the complexes derived from L3 (5-7) have dinuclear 18-membered macrocyclic structures of the composition [{R2Sn(L3-dtc)}2]. For the remaining compounds, it could not be established with certainty whether the structures are macrocyclic or polymeric. A theoretical investigation at the B3LYP/SBKJC(d,p) level of theory indicated that the alpha-AA-dtc complexes might have trinuclear macrocyclic structures. The macrocyclic complexes 5-7 have a double-calix-shaped conformation with two cavities large enough for the inclusion of aliphatic and aromatic guest molecules. They are self-complementary for the formation of supramolecuar synthons that give rise to 1D molecular arrangements in the solid state. Preliminary recognition experiments with tetrabutylammonium acetate have shown that the [{R2Sn(L3-dtc)}2] macrocycles 6 and 7 might interact simultaneously with anions (AcO(-)), which coordinate to the tin atoms, and organic cations (TBA(+)), which accommodate within the hydrophobic cavity (ion-pair recognition).
Assuntos
Aminoácidos/química , Compostos Macrocíclicos/química , Compostos Orgânicos de Estanho/química , Tiocarbamatos/química , Ânions/química , Cátions/química , Cristalografia por Raios X , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Compostos Macrocíclicos/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos Orgânicos de Estanho/síntese química , Espectrofotometria Infravermelho , Termogravimetria , Tiocarbamatos/síntese químicaRESUMO
A bis(dithiocarbamato)copper(II) complex (CuDTC2) was built on Au{111} surfaces (sheets and electrode beads) using different building blocks in a layer-by-layer (LbL) procedure. The process was followed by AFM and cyclic voltammetry. Initially 4-piperidinemethanethiol, which was synthesized here for the first time, was self-assembled on a gold surface and a highly organized array was obtained. The resulting monolayer was treated with CS2 and NH3 to transform the NH groups of piperidine into dithiocarbamate groups (DTC) with the formation of an amphiphilic ligand (DTCpipS) with thiolate and DTC terminal anionic groups. Two reductive desorption peaks were observed in the cyclic voltammogram of self-assembled DTCpipS, a more intense peak at -0.87 V (thiolate group) and a broader, less intense peak at -0.68 V, corresponding to the desorption of the DTC group bound to the gold surface after the ligand made a approximately 180 degrees flip on the surface. Copper(II) and the morpholyldithiocarbamate anion were associated with self-assembled DTCpipS in order to complete the formation of the CuDTC2 complex on the gold surface. In the voltammogram of the LbL self-assembled CuDTC2 complex the reductive desorption peak at -0.68 V disappeared and one single peak was observed at -0.85 V. This corresponds to the reorientation of all of the DTCpipS dianions in order to coordinate to copper(II) through the DTC groups, leaving the self-assembly only through the thiolate groups. The complete formation of the LbL self-assembled CuDTC2 complex was confirmed by XPS and ToF SIMS, with a detected fragment corresponding to the whole complex.
Assuntos
Cobre/química , Ouro/química , Compostos Organometálicos/síntese química , Tiocarbamatos/síntese química , Lipossomas Unilamelares/síntese química , Espectrometria de Massas , Microscopia de Força AtômicaRESUMO
In this work, we have used molecular modeling and QSAR tools to study 18 dithiocarbamate suppressors of the growth of Trypanosoma cruzi epimastigotes, which have been reported in the literature as superoxide dismutase (SOD) inhibitors. The principal component analysis (PCA) showed that the descriptors superficial area, heat of formation, logarithm of the partition coefficient, charge of the nitrogen atom from the dithiocarbamate group and Charges of the two carbon atoms adjacent to that nitrogen are responsible for the classification between the higher and lower trypanomicid activity. Using multiple linear regression (MLR) and docking methods it was possible to identify the probable bioactive isomers that suppress of the growth of T. cruzi epimastigotes. Our best partial least square (PLS) model obtained with these six descriptors yields a good correlation between experimental and predicted biological activities and compares two different SODs as possible target for interaction with the dithiocarbamates.