121505-93-9Relevant articles and documents
Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines
Oukoloff, Killian,Kovalevich, Jane,Cornec, Anne-Sophie,Yao, Yuemang,Owyang, Zachary A.,James, Michael,Trojanowski, John Q.,Lee, Virginia M.-Y.,Smith, Amos B.,Brunden, Kurt R.,Ballatore, Carlo
, p. 2180 - 2183 (2018)
The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.
Fused and bridged bi- and tri-cyclic lactams via sequential metallo-azomethine ylide cycloaddition-lactamisation
Blaney, Paul,Grigg, Ronald,Rankovic, Zoran,Thornton-Pett, Mark,Xu, Juan
, p. 1719 - 1737 (2002)
Aldimines of α-amino esters derived from aldehydes bearing an α-, β- or γ-protected amino group undergo AgOAc/R3N catalysed cycloaddition to electronegative olefins (dipolarophile). Subsequent unmasking of the amino group and lactamisation, spontaneous in most cases, generates 5-7 membered fused and bridged bi- and tri-cyclic lactams. The regioselectivity of the lactamisation is controlled by appropriate choice of the dipolarophile.
Synthesis and kinetic evaluation of ethyl acrylate and vinyl sulfone derived inhibitors for human cysteine cathepsins
Breuer, Christian,Lemke, Carina,Schmitz, Janina,Bartz, Ulrike,Gütschow, Michael
, p. 2008 - 2012 (2018)
A series of inhibitors targeting human cathepsins have been designed and synthesized following a combinatorial approach. The compounds bear an α,β-unsaturated phenyl vinyl sulfone or ethyl acrylate warhead and a peptidomimetic portion aligned to the non-primed binding region. Biochemical evaluation toward four human cathepsins was carried out and the kinetic characterization confirmed an irreversible mode of inhibition. Compound 6c combining the most advantageous building blocks for cathepsin S inhibition was identified as a potent cathepsin S inactivator exhibiting a second-order rate constant of 30600 M?1 s?1.
Inhibition of Human Neutrophil Elastase. 3. An Orally Active Enol Acetate Prodrug
Burkhart, Joseph P.,Koehl, Jack R.,Mehdi, Shujaath,Durham, Sherrie L.,Janusz, Michael J.,et al.
, p. 223 - 233 (1995)
Several analogs of N--L-valyl-N--L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE).Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1.In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo.The ED50 value for (E)-N--L-valyl-N--L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.
Bioactive pseudopeptidic analogues and cyclostereoisomers of osteogenic growth peptide C-terminal pentapeptide, OGP(10-14)
Chen, Yu-Chen,Muhlrad, Andras,Shteyer, Arie,Vidson, Marina,Bab, Itai,Chorev, Michael
, p. 1624 - 1632 (2002)
The osteogenic growth peptide (OGP) is a key factor in the mechanism of the systemic osteogenic response to local bone marrow injury. When administered in vivo, OGP stimulates osteogenesis and hematopoiesis. The C-terminal pentapeptide OGP(10-14) is the minimal amino acid sequence that retains the full OGP-like activity. Apparently, it is also the physiologic active form of OGP. Residues Tyr10, Phe12, Gly13, and Gly14 of OGP are essential for the OGP(10-14) activity. The present study explored the functional role of the peptide bonds, carboxyl and amino terminal groups, and conformational freedom in OGP(10-14). Transformations replacing the peptide bonds with surrogates such as ψ(CH2NH), ψ(CONMe), and ψ(CH2CH2) demonstrated that amide bonds do not contribute significantly to OGP(10-14) bioactivity. End-to-end cyclization yielded the fully bioactive cyclic pentapeptide c(Tyr-Gly-Phe-Gly-Gly). The retroinverso analogue c(Gly-Gly-phe-Gly-tyr), a cyclostereoisomer of c(Tyr-Gly-Phe-Gly-Gly), is at least as potent as the parent cyclic pentapeptide. The unique structure-activity relations revealed in this study suggest that the spatial presentation of the Tyr and Phe side chains has a major role in the productive interaction of OGP(10-14) and its truncated and conformationally constrained analogues with their cognate cellular target.
Peptide nucleic acids with a flexible secondary amine in the backbone maintain oligonucleotide binding affinity
Myers, Michael C.,Pokorski, Jonathan K.,Appella, Daniel H.
, p. 4699 - 4702 (2004)
(Chemical Equation Presented) Replacing a secondary amide in a peptide nucleic acid backbone with a more flexible secondary amine affords an oligomer that surprisingly maintains the same binding affinity to complementary oligonucleotides as the unmodified polyamide oligomer.
Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties
Ahn, Gang,Lansiaux, Amélie,Goossens, Jean-Fran?ois,Bailly, Christian,Baldeyrou, Brigitte,Schifano-Faux, Nadège,Grandclaudon, Pierre,Couture, Axel,Ryckebusch, Adina
, p. 8119 - 8133 (2010)
Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n = 2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n = 3 provided the highest DNA binding. Arginine derivative 32 (n = 2, series II) and glycine derivative 34 (n = 2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC50 values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC50 values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved.
Remarkable three-step-one-pot solution phase preparation of novel imidazolines utilizing a UDC (Ugi/de-Boc/cyclize) strategy
Hulme, Christopher,Ma, Liang,Romano, Joseph,Morrissette, Matthew
, p. 7925 - 7928 (1999)
This communication reveals the novel solution phase synthesis of an array of biologically relevant imidazolines in a remarkable 'three-step-one-pot' procedure, utilizing a Ugi/de-Boc/cyclization (UDC) strategy. Transformations are carried out in excellent yield by condensation of N-Boc-α-amino-aldehydes and supporting Ugi reagents. The described protocol represents a highly attractive solution phase procedure for the rapid generation of this class of molecule.
Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-Catalyzed C?H Glycosylation of Alkenes
Chen, Gong,He, Gang,Qiao, Tianjiao,Sun, Qikai,Wang, Quanquan,Zhang, Huixing
, p. 19620 - 19625 (2021)
C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C?H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C?H bond of allylamines and the δ C?H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.
Construction of combinatorial chemical libraries using a rapid and efficient solid phase synthesis based on a multicomponent condensation reaction
Kim, Sang Woong,Bauer, Shawn M.,Armstrong, Robert W.
, p. 6993 - 6996 (1998)
A 96 member library of acylated dipeptides based on a known anticonvulsant was synthesized utilizing an Ugi four component condensation followed by derivitization through nucleophilic displacement of a Weinreb type amide. The library afforded compounds in reasonable yield and high purity after cleavage from solid support.
