109927-44-8Relevant articles and documents
Inverse γ-Turn-Inspired Peptide: Synthesis and Analysis of Segetalin A Indole Hemiaminal
Lamping, Matthias,Enck, Sebastian,Geyer, Armin
, p. 7443 - 7448 (2015)
Substitution of a peptide bond for an imine transforms the irreversible macrocyclization of peptides into a reversible process. The inherent cyclization tendency of a linear peptide is then analyzable through the equilibrium between the aldehyde and the imine by virtue of the higher reactivity of the corresponding linear peptide aldehyde. The tryptophan side chain of segetalin A aldehyde forms a 12-membered cyclic indole hemiaminal instead of the 18-membered macrocyclic imine expected. Herein, we analyzed this uncommon hemiaminal that shows that the biosynthesis of cyclic peptides is not necessarily based on linear precursor peptides with a high inherent macrolactamization tendency. By substituting a peptide bond for an imine, the cyclization tendency of a linear peptide can be analyzed through equilibration of the aldehyde and imine forms. The tryptophan side chain of segetalin A aldehyde forms a 12-membered cyclic indole hemiaminal instead of the expected 18-membered macrocyclic imine. Herein, we analyze this uncommon hemiaminal.
Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors
Nakashima, Hitomi,Uto, Yoshihiro,Nakata, Eiji,Nagasawa, Hideko,Ikkyu, Kazuhiro,Hiraoka, Noriko,Nakashima, Kouichiro,Sasaki, Yuki,Sugimoto, Hiroshi,Shiro, Yoshitsugu,Hashimoto, Toshihiro,Okamoto, Yasuko,Asakawa, Yoshinori,Hori, Hitoshi
, p. 8661 - 8669 (2008)
We have designed and synthesized new hypoxic-neoplastic cells-targeted indoleamine 2,3-dioxygenase (IDO) inhibitors. 1-Methyl-tryptophan (1MT)-tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-dioxide) hybrid inhibitors including 1 (TX-2236), 2 (TX-2235), 3 (TX-2228), and 4 (TX-2234) were prepared. All of these compounds were uncompetitive IDO inhibitors. TPZ-monoxide hybrids 1 and 3 showed higher IDO inhibitory activities than TPZ hybrids 2 and 4. Among these hybrids, hybrid 1 was the most potent IDO inhibitor. TPZ hybrids 2 and 4 showed stronger hypoxia-selective cytotoxicity than TPZ to EMT6/KU cells. These data suggest that TPZ hybrids 2 and 4 may act through their dual biological functions: first, they function as hypoxic cytotoxins in hypoxic cells, and then are metabolized to their TPZ-monoxide (3-amino-1,2,4-benzotriazine 1-oxide) hybrids, which function as IDO inhibitors.
Dendritic biomimicry: Microenvironmental hydrogen-bonding effects on tryptophan fluorescence
Koenig, Stephanie,Mueller, Lars,Smith, David K.
, p. 979 - 986 (2001)
Two series of dendritically modified tryptophan derivatives have been synthesised and their emission spectra measured in a range of different solvents. This paper presents the syntheses of these novel dendritic structures and discusses their emission spectra in terms of both solvent and dendritic effects. In the first series of dendrimers, the NH group of the indole ring is available for hydrogen bonding, whilst in the second series, the indole NH group has been converted to NMe. Direct comparison of the emission wavelengths of analogous NH and NMe derivatives indicates the importance of the Kamlet-Taft solvent β parameter, which reflects the ability of the solvent to accept a hydrogen bond from the NH group, an effect not possible for the NMe series of dendrimers. For the NH dendrimers, the attachment of a dendritic shell to the tryptophan subunit leads to a red shift in emission wavelength. This dendritic effect only operates in non-hydrogen bonding solvents. For the NMe dendrimers, however, the attachment of a dendritic shell has no effect on the emission spectra of the indole ring. This proves the importance of hydrogen bonding between the branched shell and the indole NH group in causing the dendritic effect. This is the first time a dendritic effect has been unambiguously assigned to individual hydrogen-bonding interactions and indicates that such intramolecular interactions are important in dendrimers, just as they are in proteins. Furthermore, this paper sheds light on the use of tryptophan residues as a probe of the microenvironment within proteins - in particular, it stresses the importance of hydrogen bonds formed by the indole NH group.
Mild deprotection of the: N-tert -butyloxycarbonyl (N -Boc) group using oxalyl chloride
Awuah, Samuel G.,George, Nathaniel,Ofori, Samuel,Parkin, Sean
, p. 24017 - 24026 (2020/07/23)
We report a mild method for the selective deprotection of the N-Boc group from a structurally diverse set of compounds, encompassing aliphatic, aromatic, and heterocyclic substrates by using oxalyl chloride in methanol. The reactions take place under room temperature conditions for 1-4 h with yields up to 90percent. This mild procedure was applied to a hybrid, medicinally active compound FC1, which is a novel dual inhibitor of IDO1 and DNA Pol gamma. A broader mechanism involving the electrophilic character of oxalyl chloride is postulated for this deprotection strategy. This journal is
Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors
Kavanagh, Madeline E.,Gray, Janine L.,Gilbert, Sophie H.,Coyne, Anthony G.,McLean, Kirsty J.,Davis, Holly J.,Munro, Andrew W.,Abell, Chris
supporting information, p. 1924 - 1935 (2016/10/06)
The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.
Synthesis of pyrroloindolines and furoindolines via cascade dearomatization of indole derivatives with carbenium ion
Liu, Chuan,Yin, Qin,Dai, Li-Xin,You, Shu-Li
supporting information, p. 5971 - 5974 (2015/03/30)
A highly efficient intermolecular cascade dearomatization of substituted indoles with benzodithiolylium tetrafluoroborate has been developed. This reaction provides a novel strategy to synthesise C3 methyl-substituted pyrroloindolines and furoindolines under mild reaction conditions, the utility of which has been demonstrated by the synthesis of esermethol and physovenine in a highly concise manner.
NOVEL 5-SUBSTITUTED INDOLE DERIVATIVES AS DIPEPTIDYL PEPTIDASE IV (DPP-IV) INHIBITORS
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Page/Page column 102-103, (2008/06/13)
The present invention relates to 5-substituted indole derivatives of formula (I): having inhibitory potential of dipeptidyl peptidase IV (DPP IV) enzyme where x and R1 are defined as defined in the specification
Matrix metalloproteinase inhibitors: A structure-activity study
Levy, Daniel E.,Lapierre, France,Liang, Weisheng,Ye, Wenqing,Lange, Christopher W.,Li, Xiaoyuan,Grobelny, Damian,Casabonne, Marie,Tyrrell, David,Holme, Kevin,Nadzan, Alex,Galardy, Richard E.
, p. 199 - 223 (2007/10/03)
Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids inaddition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (2) Potent inhibitorsmust possess string zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustratedby itsability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.
