76220-95-6Relevant articles and documents
Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: A Reactive Group for Targeted Covalent Inhibitor Design
Erbay, Tu??e G.,Dempe, Daniel P.,Godugu, Bhaskar,Liu, Peng,Brummond, Kay M.
, p. 11926 - 11936 (2021/09/02)
Kinase activity can be modulated reversibly or irreversibly by the reaction of targeted covalent inhibitors with nucleophilic residues in protein active sites. Herein, we present thiol reactivity studies that support α-methylene-γ-lactams as tunable surro
Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation
Liu, Xingui,Wang, Yingying,Zhang, Xuan,Gao, Zhengya,Zhang, Suping,Shi, Peizhong,Zhang, Xin,Song, Lin,Hendrickson, Howard,Zhou, Daohong,Zheng, Guangrong
, p. 3925 - 3938 (2018/06/19)
Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.
Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare
Delong, Wang,Lanying, Wang,Yongling, Wu,Shuang, Song,Juntao, Feng,Xing, Zhang
, p. 286 - 307 (2017/03/09)
In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50?=?10.4?μM but less cytotoxic activity with IC50?=?141.2?μM (against HepG2 cell line) and 161.2?μM (against human hepatic L02?cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C.?orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure–activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.
COMPOSITIONS AND METHODS FOR SELECTIVELY DEPLETING SENESCENT CELLS
-
, (2016/02/26)
The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.
Synthesis, Characterization, and Evaluation of Cytotoxicity of Poly(3-methylene-2-pyrrolidone)
Heyns, Ingrid M.,Pfukwa, Rueben,Klumperman, Bert
, p. 1795 - 1800 (2016/07/06)
The homo- and copolymerization of 3-methylene-2-pyrrolidone (3M2P) is introduced. 3M2P is readily polymerized via conventional free radical polymerization, and two reversible deactivation radical polymerization methods including reversible addition-fragmentation (chain) transfer and single-electron-transfer living radical polymerization. Poly(3M2P) has a high thermal stability and a very high glass transition temperature. Poly(3M2P) does not dissolve in most common organic solvents, but it has a high aqueous solubility. Cytotoxicity tests reveal that it is nontoxic to cells, even up to concentrations of 1 mg/mL. This adds poly(3M2P) to the family of water-soluble and biocompatible pyrrolidone-based vinyl polymers.
Efficient synthesis of an A-B-C-tricycle fragment for a structural model of tolyporphin
Hu, Bing C.,Zhou, Wei Y.,Liu, Zu L.,Cai, Chao J.,Xu, Shi C.
scheme or table, p. 89 - 100 (2010/11/18)
An efficient stereocontrolled synthesis of an A-B-C-tricycle fragment 7 for a structural model of tolyporphin 3 is described. All the rings were prepared from readily available starting materials. One of the two key steps is a selective ring-opening reaction of the lactone cycle in bicyclolactam-lactone 17 to cyanopyrrolidone 18, which introduces the chirality into synthetic compounds. The other key step is the combination of A ring with B-C-bicycle via a two-time Eschenmoser sulfide contraction. A-B-C-tricycle fragment 7 allows a new approach toward tolypophin compounds and other uroporphinoids.
Efficient synthesis of 3-methylene-2-pyrrolidinone and highly exoselective diels-alder addition to cyclopentadiene
Fotiadu, Frederic,Pardigon, Olivier,Buono, Gerard,Le Corre, Maurice,Hercouet, Alain
, p. 867 - 870 (2007/10/03)
A new efficient synthesis of 3-methylene 2-pyrrolidinone 1 involving ylide-lactame 6 is reported. Diels-Alder cycloadditions of 1 to cyclopentadiene exhibited very high exoselectvities, regardless Of the experimental conditions. These results confirm the generality of exoselectivity for conformationally restricted s-cis dienophiles and indicate that the dienophile functionality and dipole moment have little influence on its magnitude.
Synthesis and Angiotensin-Converting Enzyme Inhibitory Activity of 3-(Mercaptomethyl)-2-oxo-1-pyrrolidineacetic Acids and 3-(Mercaptomethyl)-2-oxo-1-piperidineacetic Acids
Klutchko, Sylvester,Hoefle, Milton L.,Smith, Ronald D.,Essenburg, Arnold D.,Parker, Robert B.,et al.
, p. 104 - 109 (2007/10/02)
A number of γ- and δ-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared.The structures of these compounds were designed to include many of the important features of captopril.The
