Novel guanidine derivatives targeting leukemia as selective Src/Abl dual inhibitors: Design, synthesis and anti-proliferative activity.

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.

A continuous reaction network that produces RNA precursors.

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.

Design and synthesis of cyanamides as potent and selective N-acylethanolamine acid amidase inhibitors.

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.

Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design, synthesis, anti-inflammatory evaluation, ulcerogenic liability and docking study.

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.

Recent Advances in Cyanamide Chemistry: Synthesis and Applications.

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.

Cytotoxicity and cellular response mechanisms of water-soluble platinum(II) complexes of lidocaine and phenylcyanamide derivatives.

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.

[Effect of calcium cyanamid synthetic drug on Schistosoma japonicum egg morphology].

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.

Continuous synthesis of peralkylated imidazoles and their transformation into ionic liquids with improved (electro)chemical stabilities.

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.

Atom efficient cyclotrimerization of dimethylcyanamide catalyzed by aluminium amide: a combined experimental and theoretical investigation.

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.

Cobalt-mediated cyclotrimerisation of bis-alkynes and cyanamides.

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

Dihydropiperazine neonicotinoid compounds. Synthesis and insecticidal activity.

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.

Novel and efficient synthesis of 4-dimethylamino-2-glycosylaminoquinazolines by cyclodesulfurization of glycosyl thioureas with dimethylcyanamide.

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.

Synthesis of allyl cyanamides and N-cyanoindoles via the palladium-catalyzed three-component coupling reaction.

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.

Convenient syntheses of symmetrical and unsymmetrical glycosyl carbodiimides and N,N-bis(glycosyl)cyanamides.

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.

Acyl, N-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide.

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.