- Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents
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The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Patel, Sagar P.,Sinha, Anshuman,Kansara, Deep D.,Mecwan, Annie R.,Patel, Sarvangee B.,Upadhyay, Pragnesh N.,Patel, Kishan B.,Shah, Dharti B.,Prajapati, Navnit K.,Murumkar, Prashant R.,Patel, Kirti V.,Yadav, Mange Ram
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p. 3635 - 3661
(2019/08/20)
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- Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma
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Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.
- Ghedira, Donia,Voissière, Aurélien,Peyrode, Caroline,Kraiem, Jamil,Gerard, Yvain,Maubert, Elise,Vivier, Magali,Miot-Noirault, Elisabeth,Chezal, Jean-Michel,Farhat, Farhat,Weber, Valérie
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supporting information
p. 51 - 67
(2018/09/13)
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- Applications of dynamic combinatorial chemistry for the determination of effective molarity
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A new strategy for determining thermodynamic effective molarities (EM) for macrocylisation reactions using dynamic combinatorial chemistry under dilute conditions is presented. At low concentrations, below the critical value, Dynamic Libraries (DLs) of bifunctional building blocks contain only cyclic species, so it is not possible to quantify the equilibria between linear and cyclic species. However, addition of a monofunctional chain stopper can be used to promote the formation of linear oligomers allowing measurement of EM for all cyclic species present in the DL. The effectiveness of this approach was demonstrated for DLs generated from mixtures of 1,3-diimine calix[4]arenes, linear diaminoalkanes and monoaminoalkanes. For macrocycles deriving from one bifunctional calixarene and one diamine, there is an alternating pattern of EM values with the number of methylene units in the diamine: odd numbers give significantly higher EMs than even numbers. For odd numbers of methylene units, the alkyl chain can adopt an extended all anti conformation, whereas for even numbers of methylene units, gauche conformations are required for cyclisation, and the associated strain reduces EM. The value of EM for the five-carbon linker indicates that this macrocycle is a strainless ring. This journal is
- Ciaccia, Maria,Tosi, Irene,Baldini, Laura,Cacciapaglia, Roberta,Mandolini, Luigi,Di Stefano, Stefano,Hunter, Christopher A.
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p. 144 - 151
(2015/02/19)
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- Cytotoxic Glycosylated Fatty Acid Amides from a Stelletta sp. Marine Sponge
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We have discovered new glycosylated fatty acid amides, stellettosides, from a Stelletta sp. marine sponge. They were detected through LC-MS analysis of the extract combined with the cytotoxicity assay of the prefractionated sample. Their planar structures were determined by analyses of the NMR and tandem FABMS data. Stellettosides A1 and A2 (1 and 2) as well as stellettosides B1-B4 (3-6) were obtained as inseparable mixtures. Careful analysis of the NMR and tandem FABMS data of each mixture, along with comparison of the tandem FABMS data with that of a synthetic model compound, permitted us to assign the structure of the constituents in the mixture. The absolute configuration of the monosaccharide unit was determined by LC-MS after chiral derivatization. The relative configurations of the vicinal oxygenated methines in the fatty acid chains were assigned by the 1H NMR data of the isopropylidene derivative. The mixture of stellettosides B1-B4 (3-6) exhibit moderate cytotoxic activity against HeLa cells with an IC50 value of 9 ΜM, whereas the mixture of stellettosides A1 and A2 (1 and 2) was not active at a concentration of 10 ΜM.
- Peddie, Victoria,Takada, Kentaro,Okuda, Shujiro,Ise, Yuji,Morii, Yasuhiro,Yamawaki, Nobuhiro,Takatani, Tomohiro,Arakawa, Osamu,Okada, Shigeru,Matsunaga, Shigeki
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supporting information
p. 2808 - 2813
(2015/12/09)
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- Ruthenium/imidazolylphosphine catalysis: Hydrogenation of aliphatic and aromatic nitriles to form amines
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A convenient and efficient catalyst system for the hydrogenation of aliphatic nitriles towards the corresponding primary amines in high to excellent yields is presented. In addition, aromatic nitriles are reduced smoothly, too. The use of low catalyst loadings and molecular hydrogen make this protocol an attractive methodology. It's not complicated: A general and easy homogeneous catalyst system based on [Ru(cod)(methylallyl)2] and a cyclohexyl-substituted imidazolylphosphine ligand for selective hydrogenation of aliphatic nitriles is presented. In addition, by using an isopropyl-substituted imidazolylphosphine ligand, selected aromatic nitriles were reduced with excellent yields towards the primary amine. Furthermore, two new crystal structures give an insight of possible pre-catalysts.
- Werkmeister, Svenja,Junge, Kathrin,Wendt, Bianca,Spannenberg, Anke,Jiao, Haijun,Bornschein, Christoph,Beller, Matthias
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supporting information
p. 4227 - 4231
(2014/05/06)
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- Reduction of nitriles to amines with H2 catalyzed by nonclassical ruthenium hydrides - Water-promoted selectivity for primary amines and mechanistic investigations
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Catalytic hydrogenation of nitriles to amines by nonclassical ruthenium hydride complexes derived from PNP pincer ligands is described. Aromatic as well as aliphatic nitriles are reduced to the corresponding primary amines. Hydrogen pressure influences the selectivity for the primary amines. The mechanism of nitrile reduction with nonclassical ruthenium hydride pincer complexes is investigated by DFT calculations. A catalytic cycle involving the coordination of nitrile trans to the pincer backbone after an initial hydride rearrangement at the ruthenium center, and the subsequent first transfer of the hydride ligand to the carbon center of the nitrile ligand is suggested as a possible reaction mechanism. Interestingly, the use of water as additive increases the selectivity for the primary amines and the rate of the reactions. Selective synthesis of primary amines by the catalytic hydrogenation of nitriles with nonclassical ruthenium hydride pincer complexes is reported. Use of water as additive increases the selectivity and rate of the reactions. Possible catalytic cycles were identified for this important reaction of industrial significance by means of DFT calculations. Copyright
- Gunanathan, Chidambaram,Hoelscher, Markus,Leitner, Walter
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experimental part
p. 3381 - 3386
(2011/09/20)
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- New quaternary ammonium oxicam derivatives: synthesis and in vitro antiosteoarthritis evaluation
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A series of new oxicam derivatives bearing a quaternary ammonium (QA) moiety was synthesized and evaluated in vitro for antiosteoarthritis properties. Propyltrimethyl ammonium 3 and propyldiethylmethyl ammonium 11 stimulated aggrecan expression and mitigated the inhibitory action of IL-1. QA derivative 3 also increased TGF-β2 and type II receptor expression. These results suggest that such derivatives may not only inhibit the osteoarthritis degradation process but also stimulate its regeneration. QA derivatives 3 and 11 offer potential for developing new therapeutic approaches to osteoarthritis treatment.
- Vidal, Aurelien,Chezal, Jean-Michel,Mounetou, Emmanuelle
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experimental part
p. 405 - 410
(2010/04/04)
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- 1,1-dioxo-2h-1,2-benzothiazine-3-carboxamide derivatives,method for preparing same and pharmaceutical compositions comprising same
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1wherein: represents a single or double bond, R1 represents a hydrogen atom or a hydroxy, alkoxy, acyloxy, alkylsulphonyloxy, arylsulphonyloxy or arylalkoxy group, R2 represents a hydrogen atom or an alkyl group, R3 and R4, which may be identical or different, each represent a hydrogen atom, a halogen atom or an alkyl, hydroxy or alkoxy group, Ak represents an alkylene chain, R5, R6 and R7, which may be identical or different, each represent an alkyl group, or R5, R6 and R7, taken together with the nitrogen atom carrying them, form a saturated or unsaturated nitrogen-containing heterocycle, X represents a halogen atom, and its optical isomers when they exist. Medicaments.
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Page/Page column 4
(2008/06/13)
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- Regioselective covalent modification of hemoglobin in search of antisickling agents
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Although the molecular defect in sickle hemoglobin that produces sickle cell disease has been known for decades, there is still no effective drug treatment that acts on hemoglobin itself. In this work, a series of diversely substituted isothiocyanates (R-NCS) were examined for their regioselective reaction with hemoglobin in an attempt to alter the solubility properties of sickle hemoglobin. Electrospray mass spectrometry, molecular modeling, X-ray crystallography, and conventional protein chemistry were used to study this regioselectivity and the resulting increase in solubility of the modified hemoglobin. Depending on the attached R-group, the isothiocyanates were found to react either with the Cysβ93 or the N-terminal amine of the α-chain. One of the most effective compounds in the series, 2-(N,N-dimethylamino)ethyl isothiocyanate, selectively reacts with the thiol of Cysβ93 which, in conjunction with the cationic group, was seen to perturb the local hemoglobin structure. This modified HbS shows an approximately 30% increase in solubility for the fully deoxygenated state, along with a significant increase in oxygen affinity. This compound and a related analogue appear to readily traverse the erythrocyte membrane. A discussion of the relation of these structural changes to inhibition of gelation is presented. The dual activities of increasing HbS oxygen affinity and directly inhibiting deoxy HbS polymerization, in conjunction with facile membrane traversal, suggest that these cationic isothiocyanates show substantial promise as lead compounds for development of therapeutic agents for sickle cell disease.
- Park, Soobong,Hayes, Brittany L.,Marankan, Fatima,Mulhearn, Debbie C.,Wanna, Linda,Mesecar, Andrew D.,Santarsiero, Bernard D.,Johnson, Michael E.,Venton, Duane L.
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p. 936 - 953
(2007/10/03)
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- A new class of histamine H3-receptor antagonists: Synthesis and structure - Activity relationships of 7,8,9,10-Tetrahydro-6H-cyclohepta[b]quinolines
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The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H3 receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H3 receptor were discovered.
- Turner, Sean C.,Esbenshade, Timothy A.,Bennani, Youssef L.,Hancock, Arthur A.
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p. 2131 - 2135
(2007/10/03)
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- Indolin-2-one derivatives, method for preparing them and pharmaceutical compositions containing them
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PCT No. PCT/FR97/02270 Sec. 371 Date Jun. 14, 1999 Sec. 102(e) Date Jun. 14, 1999 PCT Filed Dec. 11, 1997 PCT Pub. No. WO98/25901 PCT Pub. Date Jun. 18, 1998The invention relates to compounds with formula (I), a process for their preparation and pharmaceutical compositions containing them. These compounds have an excellent affinity for vasopressin and/or oxytocin
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- Method for inhibiting angiogenesis using squalamine and squalamine steroid derivatives
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A method of inhibiting angiogenesis in a patient includes administering to the patient an effective amount of squalamine or a pharmaceutically acceptable salt of squalamine. Alternatively, a compound according to the following Formula (III) (or a pharmaceutically acceptable salt thereof) can be administered: STR1 wherein Z5 is α-H or β-H; each of the substituents Z7 is selected from the group of --H, --OH, --SH, --NH2, --F, --(C1 -C3)-alkyl, and --(C1 -C3)-alkoxy; and one of the substituents Z12 is --H and the other is --H or --OH. X' is a polyamine side chain of the formula --X1 --(CH2)p --X2 --(CH2)q --N(RII)(RIII), wherein one of X1 and X2 is --N(RIV) and the other is selected from the group of --N(RV), --O, --S, and --CH2. RIV and RV are each --H or --(C1 -C3)-alkyl, p and q are each an integer of from 0 to 5 (but both are not 0). RII and RIII in the formula for X' are each --H, --(C1 -C3)-alkyl, or --(CH2)r --N(R10)(R11) wherein r is an integer from 2 to 5 and R10 and R11 are each --H or --(C1 -C3)-alkyl. R' in Formula (III) is --H or --(C1 -C3)-alkyl, and Y' is --(C1 -C10)-alkyl, unsubstituted or substituted with --CO2 H, --OH, --NH--SO2 CF3, --SO3 H, --PO3 H2, --OSO3 H, --CF3, --F, STR2
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- Steroid derivatives, pharmaceutical compositions containing them, and their use as antibiotics or disinfectants
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Compounds having a broad range of antimicrobial activity generally have a structure including asteroid nucleus with a cationic, preferably polyamine, side chain (X) and an anionic side chain (Y). The invention is also directed to compounds of the Formula III: STR1 preferably where the steroid ring nucleus is saturated; the steroid ring substituent Z5 is α-H; one Z7 is β-H and the other is α-H or α-OH; both substituents Z12 are hydrogen; X' is a polyamine side chain of the formula --NH--(CH2)p --NH--(CH2)q --N(RII)(RIII) where p and q are each independently 3 or 4, and RII and RIII are each independently hydrogen or methyl; R' is methyl; and Y' is (C1 -C10)-alkyl substituted with a group such as --CO2 H or --SO3 H.
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- CONVENIENT ROUTES TO ALKYL-SUBSTITUTED POLYAMINES
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Alkyl-substituted polyamines, valuable for biological studies, can be prepared from N-phenylmethoxycarbonyl-1,4-diaminobutane (1b) and N-phenylmethoxycarbonyl-4-azidobutanamine (4a) by utilising the following reactions: (i) reduction of the phenylmethoxycarbonyl group to methyl by borane and (ii) combination of the Staudinger and aza-Wittig reactions .
- Golding, Bernard T.,O"Sullivan, Mary C.,Smith, Lewis L.
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p. 6651 - 6654
(2007/10/02)
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- Long-range anisotropic effects of long chain amides
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In 1H-NMR spectra of amids with long-chain aliphatic N-substituents one observes - despite of the free mobility of the aliphatic chain - splitting of the signals of the terminal methyl groups which is caused by the hindered rotation of the amide bond. - Keywords: Amides; Hindered rotation; 1H-NMR
- Budzikiewicz, Herbert,Vieth, Peter-Eric,Krueger, Uwe
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p. 825 - 840
(2007/10/02)
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