3303-84-2Relevant articles and documents
Design of Potent Protein Kinase Inhibitors Using the Bisubstrate Approach
Ricouart, A.,Gesquiere, J. C.,Tartar, A.,Sergheraet, C.
, p. 73 - 78 (1991)
A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate.Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a -NH(CH2)2NH(CH2)2CO- linker.This compound, with a Ki of 0.1 μM toward protein kinase C (PKC) and 0.004 μM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.
FeCl3·6H2O catalyzed diastereoselective synthesis of (L)-menthyl 4-oxo-2-arylpiperidine-3-carboxylates
Babu Syamala, Lakshmi V.R.,Bhat, Ramakrishna G.
, p. 4836 - 4840 (2017)
An efficient diastereoselective synthesis of substituted piperidines is accomplished by using catalytic amount of FeCl3·6H2O via intramolecular aza-Michael addition of carbamate on alkylidene β-keto (L)-menthyl esters in a very short time.
Mechanism of hemolysis and erythrocyte transformation caused by lipogrammistin-A, a lipophilic and acylated cyclic polyamine from the skin secretion of soapfishes (Grammistidae)
Kobayashi, Yoshimasa,Onuki, Hiroyuki,Tachibana, Kazuo
, p. 2073 - 2081 (1999)
The mechanism of hemolysis and erythrocyte transformation caused by lipogrammistin-A (LGA), a lipophilic and acylated cyclic polyamine from the skin secretion of soapfishes (Grammistidae), was investigated. The dependency of hemolysis on the erythrocyte concentration indicated that the amount of membrane-bound LGA required for 50% hemolysis is about 13% of the total phospholipids in erythrocytes on a molar basis. A synthetic analogue which lacked a long alkyl chain exhibited much less activity, suggesting that the alkyl chain is important for membrane-binding. In addition, microscopic observations showed that LGA elicited the invagination of erythrocytes at sublytic concentrations, which makes LGA one of the most potent agents with this transforming activity known to date. Its protonated secondary amino group is responsible for the unequal distribution of LGA in the inner leaflet of the lipid bilayer, which leads to invagination, since acetylation at the amino group markedly reduced the invagination activity. Furthermore, the size of LGA-induced lesions on erythrocyte membrane was estimated to be 7-29 A based on osmotic protection experiments, where the external addition of isotonic molecules in this size range gradually increased the effective dose of LGA. Based on these lines of evidence, the mode of LGA action on erythrocytes is deduced to be as follows. First, LGA molecules bind to erythrocyte membrane by lipophilicity. Second, the molecules accumulate in the inner leaflet of the lipid bilayer by interaction of their cationic ammonium groups with acidic residues of membrane lipid in the inner surface. This uneven distribution of LGA distorts the bilayer structure, and results in a change in cell shape and consequent small lesions. Third, small solutes permeate through the lesions, which induces an osmotic change across the membrane, which leads to colloid-osmotic rupture. This mode of action of LGA on erythrocytes accompanied by cell invagination is the first reported example for natural defense substances.
Antineoplastic Agents. 607. Emetine Auristatins
Chapuis, Jean-Charles,Melody, Noeleen,Pettit, George R.
, (2020)
The remarkable biological activity of the dolastatin 10 structural modifications quinstatins and isoquinstatins prompted further investigation into drug hybrids containing biologically active isoquinoline moieties. In this study, the isoquinoline alkaloid emetine was selected as one of the structural domains of a hybrid molecule. That was accomplished by covalently bonding the Dov-Val-Dil-Dap peptide sequence of dolastatin 10 peptide at the N-2′ secondary amine of emetine. Three new hybrids were synthesized, 5, 9, and 10. Comparison of the biological activity of these new peptide-emetine analogues with emetine showed complete retention of activity for 5 and a 10-fold decrease for hybrids 9 and 10. The result was surprising, as the activity of emetine is usually lost or greatly reduced when substituted at the N-2′ position.
COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF TUMORS
-
Page/Page column 67-68, (2021/06/22)
The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular for the use in the treatment of diseases or disorders wherein disrupting Rad51-BRCA2 interaction is beneficial.
Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease
Singh, Yash Pal,Shankar, Gauri,Jahan, Shagufta,Singh, Gourav,Kumar, Navneet,Barik, Atanu,Upadhyay, Prabhat,Singh, Lovejit,Kamble, Kajal,Singh, Gireesh Kumar,Tiwari, Sanjay,Garg, Prabha,Gupta, Sarika,Modi, Gyan
, (2021/09/04)
In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure–activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC50 = 0.96 ± 0.14 μM, BChE IC50 = 1.23 ± 0.23 μM) compared to earlier identified lead molecule EJMC-G (AChE IC50 = 5.74 ± 0.13 μM, BChE IC50 = 14.05 ± 0.10 μM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC50 = 20.25 ± 0.26 μM) over the earlier identified EJMC-B (IC50 = 61.98 ± 0.30 μM) and it also was able to chelate iron. Co-treatment of 13b with H2O2, significantly attenuated and reversed H2O2-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.
