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.
Caged cyclopropenes for controlling bioorthogonal reactivity
Kumar, Pratik,Jiang, Ting,Li, Sining,Zainul, Omar,Laughlin, Scott T.
, p. 4081 - 4085 (2018)
Bioorthogonal ligations have been designed and optimized to provide new experimental avenues for understanding biological systems. Generally, these optimizations have focused on improving reaction rates and orthogonality to both biology and other members of the bioorthogonal reaction repertoire. Less well explored are reactions that permit control of bioorthogonal reactivity in space and time. Here we describe a strategy that enables modular control of the cyclopropene-tetrazine ligation. We developed 3-N-substituted spirocyclopropenes that are designed to be unreactive towards 1,2,4,5-tetrazines when bulky N-protecting groups sterically prohibit the tetrazine's approach, and reactive once the groups are removed. We describe the synthesis of 3-N spirocyclopropenes with an appended electron withdrawing group to promote stability. Modification of the cyclopropene 3-N with a bulky, light-cleavable caging group was effective at stifling its reaction with tetrazine, and the caged cyclopropene was resistant to reaction with biological nucleophiles. As expected, upon removal of the light-labile group, the 3-N cyclopropene reacted with tetrazine to form the expected ligation product both in solution and on a tetrazine-modified protein. This reactivity caging strategy leverages the popular carbamate protecting group linkage, enabling the use of diverse caging groups to tailor the reaction's activation modality for specific applications.
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.
A synthetic tripeptide as organogelator: Elucidation of gelation mechanism
Malik, Sudip,Maji, Samir K.,Banerjee, Arindam,Nandi, Arun K.
, p. 1177 - 1186 (2002)
A new terminally protected synthetic tripeptide with noncoded amino acids, tert-butyloxycarbonyl-β-alanylα-aminoisobutyryl-β-alanyl methyl ester, is synthesized. The product is characterized by 1H NMR and DQF COSY NMR data. This tripeptide produces thermoreversible gels in 1,2-dichlorobenzene (DCB) at room temperature (30 °C). The morphology of the dried gels is studied using optical microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The micrographs show the presence of both rod like morphology and liquid-liquid phase separated morphology in the gels. Thermal study by differential scanning calorimeter (DSC-7) indicates the presence of a reversible first order phase transition during heating and cooling processes. Wide-angle X-ray scattering (WAXS) and electron diffraction experiments indicate the presence of polycrystalline materials in the gel and the crystal structure of the gel is almost the same as that of the pure tripeptide. Solvent subtracted Fourier transformed infra-red (FT-IR) study indicates that in the sol state there are free N-H and intramolecular hydrogen bonded N-H stretching vibrations at 3440 and 3375 cm-1, respectively. In the gel state both these vibrations shifted to 3325 and 3309 cm-1, respectively. The phase diagram of these gels, determined from both the DSC method and visually, indicates the tripeptide-DCB complexation with singular point characteristics. An attempt is made to understand the gelation mechanism of this system by measuring the gelation rate (tgel-1) using the test tube tilting method. The gelation rate (tgel-1) is expressed as tgel-1 α f(C)f(T) and the analysis of the concentration function f(C) at a particular temperature indicates that the gelation process obeys the three dimensional percolation mechanism. The microscopic mechanism of the gelation process is explored from the temperature function f(T) of the gelation rate at a particular concentration expressing f(T) in two different forms: (I) for fibrillar (rod like) crystallization and (II) for spinodal decomposition. A tentative structure of the tripeptide in the gel state has been proposed by molecular modeling using the MMX program.
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.
Formation of a large-scale ordered honeycomb pattern by an organogelator via a self-assembly process
Zhang, Mingming,Sun, Shengtong,Yu, Xudong,Cao, Xinhua,Zou, Ying,Yi, Tao
, p. 3553 - 3555 (2010)
We have developed a facile strategy to fabricate a large-scale, orderly-patterned honeycomb structure by using supramolecular self-assembly of a low mass organic molecule.
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.
Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo
Deng, Xuemei,Feng, Hanzhong,Feng, Yiyue,He, Yongxing,Jiang, Weifan,Li, Junfang,Li, Zhao,Liu, Dan,Lu, Yingmei,Shi, Tao,Wang, Zhen,Zhang, Honghua,Zhang, Jian
, (2021/10/12)
Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.
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.
Tricomponent Supramolecular Multiblock Copolymers with Tunable Composition via Sequential Seeded Growth
Agasti, Sarit S.,Das, Angshuman,George, Subi J.,Sarkar, Aritra,Sasmal, Ranjan,Venugopal, Akhil
supporting information, p. 18209 - 18216 (2021/07/10)
Synthesis of supramolecular block co-polymers (BCP) with small monomers and predictive sequence requires elegant molecular design and synthetic strategies. Herein we report the unparalleled synthesis of tri-component supramolecular BCPs with tunable microstructure by a kinetically controlled sequential seeded supramolecular polymerization of fluorescent π-conjugated monomers. Core-substituted naphthalene diimide (cNDI) derivatives with different core substitutions and appended with β-sheet forming peptide side chains provide perfect monomer design with spectral complementarity, pathway complexity and minimal structural mismatch to synthesize and characterize the multi-component BCPs. The distinct fluorescent nature of various cNDI monomers aids the spectroscopic probing of the seeded growth process and the microscopic visualization of resultant supramolecular BCPs using Structured Illumination Microscopy (SIM). Kinetically controlled sequential seeded supramolecular polymerization presented here is reminiscent of the multi-step synthesis of covalent BCPs via living chain polymerization. These findings provide a promising platform for constructing unique functional organic heterostructures for various optoelectronic and catalytic applications.
