Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of linkage geometry on biological activity in thiourea- and guanidine-substituted acridines and platinum-acridines.

ABSTRACT: Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4', resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 cells. Conjugate 4' represents a new chemotype with potential applications in the treatment of chemoresistant tumors.

SUBMITTER: Ma Z

PROVIDER: S-EPMC2474763 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Effect of linkage geometry on biological activity in thiourea- and guanidine-substituted acridines and platinum-acridines.

Ma Zhidong Z Saluta Gilda G Kucera Gregory L GL Bierbach Ulrich U

Bioorganic & medicinal chemistry letters 20080516 13

Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4', resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 c ...[more]

PMID: 18515101

Similar Datasets

Cyclic enkephalins with a diversely substituted guanidine bridge or a thiourea bridge: synthesis, biological and structural evaluations.

Project description:Two series of 22 and 15 atom cyclic enkephalins incorporating a diversely substituted guanidine bridge have been prepared to assess the potential effect of the bridge substitutions on their opioid activity profile. The most notable results were obtained with the shortest cyclic analogues, which showed a significant variation of their binding affinity toward ? and ? opioid receptors in relation to bridge substitution. NMR studies were performed to rationalize these data. Some small analogues were found to exist as at least one major and one minor stable forms, which could be separated by chromatography. In particular, the compounds 13 and 14 with a cyclic substituent were separated in three isomers and the basis of this multiplicity was explored by 2D NMR spectroscopy. All compounds were agonists with slight selectivity for the ? opioid receptor. Compounds 7a (thiourea bridge) and 10a (N-Me-guanidine bridge) showed nanomolar affinity toward ? receptor, the latter being the more selective for this receptor (40-fold).

| S-EPMC3942877 | biostudies-literature

Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies.

Project description:The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.

| S-EPMC6272548 | biostudies-literature

Identification, synthesis and biological activity of alkyl-guanidine oligomers as potent antibacterial agents.

Project description:In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound. This serendipitous discovery led us to investigate the chemical nature of the unknown components of the mixture. Through MS analysis coupled with design and synthesis we found that the components were spontaneously generated oligomers of the original compound. Preliminary biological evaluations eventually confirmed the broad-spectrum antibacterial activity of this new family of molecules. Interestingly the symmetric dimeric derivative (2) exhibited the best profile and it was selected as lead compound for further studies.

| S-EPMC5557985 | biostudies-literature

Synthesis, reactivity, and biological activity of gold(I) complexes modified with thiourea-functionalized tyrosine kinase inhibitors.

Project description:Thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as potential receptor-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the epidermal growth factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib. Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex [{Au(?-7-S,N)}2]X2 (X = Cl(-), SCN(-)) (12a,b) (X-ray crystallography, electrospray mass spectrometry). Derivative 9 forms a stable linear complex, [Au(PEt3)(9-S)](NO3) (13). The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. Compound 9 partially overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 ?M, respectively). The corresponding gold complex (13) maintains activity in the low-micromolar concentration range similar to the metal-free carrier. Compound 9 and the corresponding [Au(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar IC50 values similar to those observed for gefitinib under the same assay conditions. Potential mechanisms of action and reactions in biological media of this new type of hybrid agent, as well as shortcomings of the current design are discussed.

| S-EPMC4450862 | biostudies-literature

Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions.

Project description:Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.

| S-EPMC6968486 | biostudies-literature

Selective recovery of platinum from spent autocatalyst solution by thiourea modified magnetic biocarbons.

Project description:The precious platinum group metals distributed in urban industrial products should be recycled because of their rapid decline in the contents through excessive mining. In this work, thiourea modified magnetic biocarbons are prepared via an energy-efficient microwave-assisted activation and assessed as potential adsorbents to recover platinum ions (i.e., Pt(IV)) from dilute waste solution. The physicochemical properties of prepared biocarbons are characterized by a series of spectroscopic and analytic instruments. The adsorption performance of biocarbons is carried out by using batch tests. Consequently, the maximum adsorption capacity of Pt(IV) observed for adsorbents is ca. 42.8 mg g-1 at pH = 2 and 328 K. Both adsorption kinetics and isotherm data of Pt(IV) on the adsorbents are fitted better with non-linear pseudo second-order model and Freundlich isotherm, respectively. Moreover, the thermodynamic parameters suggest that the Pt(IV) adsorption is endothermic and spontaneous. Most importantly, the adsorbents exhibit high selectivity toward Pt(IV) adsorption and preserve ca. 96.9% of adsorption capacity after six cyclic runs. After adsorption, the regeneration of the prepared adsorbents can be effectively attained by using 1 M thiourea/2% HCl mixed solution as an eluent. Combined the data from Fourier transform infrared and X-ray photoelectron spectroscopies, the mechanisms for Pt(IV) adsorption are governed by Pt-S bond between Pt(IV) and thiourea as well as the electrostatic attraction between anionic PtCl62- and cationic functional groups of adsorbents. The superior Pt(IV) recovery and sustainable features allow the thiourea modified magnetic biocarbon as a potential adsorbent to recycle noble metals from spent autocatalyst solution.

| S-EPMC8481563 | biostudies-literature

Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest ?-Secretase Enzymatic Activity Involved in Alzheimer's Disease.

Project description:Proteases BACE1 (?-secretases) enzymes have been recognized as a promising target associated with Alzheimer's disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50 = 97 ± 0.91?nM) and active to arrest (99%) ?-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p < 0.05). Improved pharmacokinetic parameters, viz., Log?P o/w (1.76), Log?S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD.

| S-EPMC7238388 | biostudies-literature

Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine.

Project description:Three platinum-chloroquine complexes, trans-Pt(CQDP)(2)(I)(2) [1], trans-Pt(CQDP)(2)(Cl)(2) [2] and trans-Pt(CQ)(2)(Cl)(2) [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.

| S-EPMC3294264 | biostudies-literature

Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro-Michael reaction: Theoretical studies on mechanism and enantioselectivity.

Project description:A new guanidine-thiourea organocatalyst has been developed and applied as bifunctional organocatalyst in the Michael addition reaction of diethyl malonate to trans-?-nitrostyrene. Extensive DFT calculations, including solvent effects and dispersion corrections, as well as ab initio calculations provide a plausible description of the reaction mechanism.

| S-EPMC3458773 | biostudies-literature

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole.

Project description:To find pesticidal lead compounds with high activity, a series of novel benzamides substituted with pyridine-linked 1,2,4-oxadiazole were designed by bioisosterism, and synthesized easily via esterification, cyanation, cyclization and aminolysis reactions. The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. The preliminary bioassay showed that most compounds had good larvicidal activities against mosquito larvae at 10 mg/L, especially compound 7a, with a larvicidal activity as high as 100%, and even at 1 mg/L was still 40%; at 50 mg/L, all the target compounds showed good fungicidal activities against the eight tested fungi. Moreover, compound 7h exhibited better inhibitory activity (90.5%) than fluxapyroxad (63.6%) against Botrytis cinereal. Therefore, this type of compound can be further studied.

| S-EPMC7435590 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data