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1.
Bioorg Chem ; 147: 107410, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38688197

RESUMO

A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, 1H-, 13C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC50 of 0.018 µM for normoxia, and 0.001 µM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC500.25 µM and Abl inhibitory activity with IC500.08 µM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC500.31 µM, VEGFR-2 IC500.68 µM, B-raf IC500.33 µM, ERK IC501.41 µM, CK1 IC500.29 µM and p38-MAPK IC500.38 µM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability.


Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-abl , Quinases da Família src , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Guanidina/farmacologia , Guanidina/química , Guanidina/síntese química , Guanidina/análogos & derivados , Células HL-60 , Leucemia/tratamento farmacológico , Leucemia/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo , Relação Estrutura-Atividade , Cianamida/síntese química , Cianamida/química , Cianamida/farmacologia
2.
Proc Natl Acad Sci U S A ; 117(24): 13267-13274, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487725

RESUMO

Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.


Assuntos
Evolução Química , Modelos Químicos , RNA/química , RNA/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/síntese química , Acetaldeído/química , Cianamida/síntese química , Cianamida/química , Raios gama , Imidazóis/síntese química , Imidazóis/química , Origem da Vida , Oxazóis/síntese química , Oxazóis/química , Fotoquímica , Água/química
3.
Bioorg Med Chem ; 28(1): 115195, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31761726

RESUMO

N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed >100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway,1-4 and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties.5-8 Our ligand design strategy followed a traditional structure-activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t1/2 > 2 h; human and rodents). The disclosed cyanamides represent promising new pharmacological tools to investigate the potential role of NAAA inhibitors and dual NAAA-FAAH inhibitors as therapeutic agents for the treatment of inflammation and pain.


Assuntos
Amidoidrolases/antagonistas & inibidores , Cianamida/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Amidoidrolases/metabolismo , Animais , Cianamida/síntese química , Cianamida/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
4.
J Enzyme Inhib Med Chem ; 32(1): 805-820, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28587532

RESUMO

Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d-f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cianamida/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Úlcera Gástrica/tratamento farmacológico , Tetrazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cianamida/síntese química , Cianamida/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Edema/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ovinos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
5.
Molecules ; 22(4)2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28417938

RESUMO

The application of alkyl and aryl substituted cyanamides in synthetic chemistry has diversified multi-fold in recent years. In this review, we discuss recent advances (since 2012) in the chemistry of cyanamides and detail their application in cycloaddition chemistry, aminocyanation reactions, as well as electrophilic cyanide-transfer agents and their unique radical and coordination chemistry.


Assuntos
Química , Cianamida/química , Catálise , Técnicas de Química Sintética , Cianamida/síntese química , Ciclização , Metais/química
6.
Biometals ; 30(1): 59-70, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27995355

RESUMO

Three new platinum(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pt(3,5-(NO2)2pcyd)2(LC)], 1, K[Pt(3,5-(CF3)2pcyd)2(LC)], 2, K[Pt(3,5-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 3,5-(NO2)2pcyd: 3,5-dinitro phenylcyanamide, 3,5-(CF3)2pcyd: 3,5-bis(trifluoromethyl) phenylcyanamide, 3,5-Cl2pcyd: 3,5-dichloro phenylcyanamide) have been synthesized and fully characterized. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. The complexes 1-3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 1 > 2 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pt(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction. The complex 1 caused to approximately 80-fold higher DNA platination level with respect to cisplatin. The complexes 1-3 can considerably stimulate the production of hydrogen peroxide in a time-dependent manner. Also, the complexes 1-3 induced an increase in reactive oxygen species (ROS) production that was superior to that induced by antimycin. The complex 1 had the most effect on ROS production in comparison with other complexes.


Assuntos
Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Compostos Organoplatínicos/química , Platina/química , Células A549 , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/química , Cianamida/síntese química , Cianamida/química , DNA/efeitos dos fármacos , Células Hep G2 , Humanos , Lidocaína/administração & dosagem , Lidocaína/síntese química , Lidocaína/química , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/síntese química , Platina/administração & dosagem , Solubilidade , Água/química
7.
Artigo em Chinês | MEDLINE | ID: mdl-26094416

RESUMO

OBJECTIVE: To study the morphological change of Schistosoma japonicum eggs processed by calcium cyanamide synthetic drug, so as to provide the basis for further study of the mechanism that calcium cyanamide synthetic drug to schistosome eggs. METHODS: The calcium cyanamide synthetic drug was added to the cattle feces containing schistosome eggs and mixed up, and then the cattle feces was stacked as original shape on the marshland. Blank controls were set at the same time. The cattle feces samples were collected and.the schistosome eggs were observed under a microscope on the 1st, 2nd, 3rd, 7th day after the experiment. RESULTS: By the effect of calcium cyanamide synthetic drug, the color of eggs was deepening gradually, the miracidia were atrophied, and the shells of eggs were thickened. The embryonic membrane of miracidia was no longer completed 3 days later, and the miracidia were deformed severely 7 days later. The atrophy of miracidia was not obvious in the blank controls. CONCLUSION: The schistosome miracidia and embryonic membrane can be damaged by the calcium cyanamide synthetic drug, and worse damaged with time extending.


Assuntos
Doenças dos Bovinos/parasitologia , Cianamida/farmacologia , Óvulo/crescimento & desenvolvimento , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/veterinária , Esquistossomicidas/farmacologia , Animais , Bovinos , Cianamida/síntese química , Fezes , Feminino , Masculino , Óvulo/efeitos dos fármacos , Schistosoma japonicum/crescimento & desenvolvimento , Esquistossomose Japônica/parasitologia , Esquistossomicidas/síntese química
8.
Chemphyschem ; 13(13): 3146-57, 2012 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-22730073

RESUMO

A versatile and efficient method to synthesize tetrasubstituted imidazoles via a one-pot modified Debus-Radziszewski reaction and their subsequent transformation into the corresponding imidazolium ionic liquids is reported. The tetrasubstituted imidazoles were also synthesized by means of a continuous flow process. This straightforward synthetic procedure allows for a fast and selective synthesis of tetrasubstituted imidazoles on a large scale. The completely substituted imidazolium dicyanamide and bis(trifluoromethylsulfonyl)imide salts were obtained via a metathesis reaction of the imidazolium iodide salts. The melting points and viscosities are of the same order of magnitude as for their non-substituted analogues. In addition to the superior chemical stability of these novel ionic liquids, which allows them to be applied in strong alkaline media, the improved thermal and electrochemical stabilities of these compounds compared with conventional imidazolium ionic liquids is also demonstrated by thermogravimetrical analysis (TGA) and cyclic voltammetry (CV). Although increased substitution of the ionic liquids does not further increase thermal stability, a definite increase in cathodic stability is observable.


Assuntos
Imidazóis/síntese química , Líquidos Iônicos/síntese química , Cianamida/síntese química , Cianamida/química , Técnicas Eletroquímicas , Imidazóis/química , Imidas/síntese química , Imidas/química , Líquidos Iônicos/química
9.
Chem Commun (Camb) ; (31): 3645-7, 2008 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-18665286

RESUMO

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.


Assuntos
Alumínio/química , Cianamida/síntese química , Altretamine/química , Catálise , Cristalografia por Raios X , Cianamida/química , Ciclização , Conformação Molecular , Termodinâmica
10.
Chem Commun (Camb) ; (21): 2394-5, 2004 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-15514782

RESUMO

CpCo(CO)2-mediated cyclotrimerisation of bis-alkynes and cyanamides provides multisubstituted 2-aminopyridines, including macrocyclic products, such as 22 (50% yield).


Assuntos
Alcinos/síntese química , Cobalto/química , Cianamida/síntese química , Compostos Organometálicos/química , Alcinos/química , Cianamida/química , Ciclização , Estrutura Molecular , Compostos Organometálicos/síntese química
11.
J Agric Food Chem ; 51(10): 3035-42, 2003 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-12720388

RESUMO

Syntheses of various isomeric dihydropiperazines can be approached successfully by taking advantage of the regioselective monothionation of their respective diones. Preparation of the precursor unsymmetrical N-substituted piperazinediones from readily available diamines is key to this selectivity. The dihydropiperazine ring system, as exemplified in 1-[(6-chloropyridin-3-yl)methyl]-4-methyl-3-oxopiperazin-2-ylidenecyanamide (4) and 1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-methyl-3-oxopiperazin-2-ylidenecyanamide (25), has been shown to be a suitable bioisosteric replacement for the imidazolidine ring system contained in neonicotinoid compounds. However, placement of the cyanoimino electron-withdrawing group further removed from the pyridine ring, as in 4-[(6-chloropyridin-3-yl)methyl]-3-oxopiperazin-2-ylidenecyanamide (3a), or relocation of the carbonyl group, as in 1-[(6-chloropyridin-3-yl)methyl]-4-methyl-5-oxopiperazin-2-ylidenecyanamide (5), results in significantly decreased bioisosterism. The dihydropiperazine ring system of 4 and 25 also lends a degree of rigidity to the molecule that is not offered by the inactive acyclic counterpart 2-[(6-chloropyridin-3-yl)-methyl-(methyl)amino]-2-(cyanoimino)-N,N-dimethylacetamide (6). A pharmacophore model is proposed that qualitatively explains the results on the basis of good overlap of the key pharmacophore elements of 4 and imidacloprid (1); the less active regioisomers of 4 (3a, 5, and 6) feature a smaller degree of overlap.


Assuntos
Anabasina/química , Moscas Domésticas/química , Inseticidas/síntese química , Piperazinas/síntese química , Animais , Afídeos , Membrana Celular/química , Cianamida/análogos & derivados , Cianamida/síntese química , Cianamida/química , Ligação de Hidrogênio , Isomerismo , Modelos Moleculares , Estrutura Molecular , Piperazinas/química , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade
12.
Chem Pharm Bull (Tokyo) ; 50(11): 1517-9, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12419923

RESUMO

4-dimethylamino-2-glycosylaminoquinazoline derivatives were synthesized by cyclodesulfurization of N-aryl-N'-glycosyl thioureas with dimethylcyanamide in the presence of silver triflate in good yields.


Assuntos
Cianamida/síntese química , Quinazolinas/síntese química , Tioureia/síntese química , Aminoquinolinas/síntese química , Aminoquinolinas/química , Cianamida/química , Quinazolinas/química , Tioureia/análogos & derivados , Tioureia/química
13.
J Am Chem Soc ; 124(40): 11940-5, 2002 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-12358538

RESUMO

The palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides, allyl methyl carbonate, and trimethylsilyl azide was conducted in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and dppe (1,2-bis(diphenylphosphino)ethane) (10 mol %). Allyl aryl cyanamides with a wide variety of functional groups were obtained in excellent yields. This palladium-catalyzed TCCR was further utilized for the synthesis of N-cyanoindoles. The reaction of 2-alkynylisocyanobenzenes, allyl methyl carbonate, and trimethylsilyl azide in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) at higher temperatures afforded N-cyanoindoles in good to allowable yields. (eta(3)-Allyl)(eta(3)-cyanamido)palladium complex, an analogue of the bis-pi-allylpalladium complex, is a key intermediate in the TCCR, and a pi-allylpalladium mimic of the Curtius rearrangement is involved to generate the (eta(3)-allyl)(eta(3)-cyanamido)palladium intermediate.


Assuntos
Cianetos/síntese química , Indóis/síntese química , Cristalografia por Raios X , Cianamida/síntese química , Cianamida/química , Cianetos/química , Indóis/química , Estrutura Molecular , Paládio/química
14.
Carbohydr Res ; 337(13): 1171-8, 2002 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-12110191

RESUMO

Reaction of glycosyl trimethylphosphinimides with carbon disulfide under mild conditions (room temperature, short reaction time) leads to symmetrical glycosyl carbodiimides. Addition of bis(trimethylsilyl)carbodiimide to peracetylated aldoses under the influence of SnCl(4) afforded N,N-bis(glycosyl)cyanamides for the first time. Readily accessible unsymmetrical N,N'-bis(glycosyl)thioureas can be desulfurated and transformed into the corresponding carbodiimides using HgO in CHCl(3)/water at room temperature.


Assuntos
Carbodi-Imidas/síntese química , Cianamida/síntese química , Glicosídeos/síntese química , Carbodi-Imidas/química , Configuração de Carboidratos , Cianamida/química , Glicosídeos/química , Estereoisomerismo
17.
J Med Chem ; 29(10): 1922-9, 1986 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3761311

RESUMO

Cyanamide (H2NC identical to N), a potent aldehyde dehydrogenase (AlDH) inhibitor that is used therapeutically as an alcohol deterrent agent, is known to be rapidly metabolized and excreted in the urine as acetylcyanamide (1). On the basis of our observation that 1 is deacetylated to cyanamide in vivo, albeit very slightly, thereby serving as a precursor of prodrug form of the latter, several acyl derivatives of cyanamide were synthesized specifically as prodrugs, including benzoylcyanamide (2), pivaloylcyanamide (3), and 1-adamantoylcyanamide (4), as well as long- and medium-chain fatty acyl derivatives such as palmitoyl- (6), stearoyl- (7), and n-butyrylcyanamide (5). N-Protected alpha-aminoacyl and peptidyl derivatives of cyanamide were also synthesized, and these include N-carbobenzoxyglycyl- (10), hippuryl- (13), N-benzoyl-L-leucyl- (14), N-carbobenzoxyglycyl-L-leucyl- (18), N-carbobenzoxy-L-pyroglutamyl- (22), L-pyroglutamyl-L-leucyl- (19), and L-pyroglutamyl-L-phenylalanylcyanamide (20). All of these prodrugs of cyanamide raised ethanol-derived blood acetaldehyde levels in rats significantly over controls 3 h after ip drug administration, and some of these were still capable of elevating blood acetaldehyde 16 h post drug administration. A selected group of cyanamide prodrugs were also evaluated by the oral route of administration and showed nearly equivalent activity as the ip route in elevating ethanol-derived blood acetaldehyde. These results suggest potential utility of these prodrugs as deterrent agents for the treatment of alcoholism.


Assuntos
Dissuasores de Álcool/síntese química , Aldeído Desidrogenase/antagonistas & inibidores , Cianamida/síntese química , Cianetos/síntese química , Acilação , Dissuasores de Álcool/farmacologia , Animais , Biotransformação , Cianamida/metabolismo , Cianamida/farmacologia , Ratos
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