logo
    Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs
    Molecular Pharmacology (2002)
    Danny BurgPeter R. WielingaNoam ZelcerTohru SAEKIGerard J. MulderPiet Borst
    35
    Citation
    40
    Reference
    10
    Related Paper
    Citation Trend
    Abstract:
    Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups [Bioorg Med Chem10:195–205, 2002]. Several of these compounds were effective inhibitors of MRP1-mediated [3H]GS-EA and [3H]E217βG transport, as studied in membrane vesicles prepared from MRP1-overproducing Sf9 cells. The modifications of the peptide backbone have distinct implications for recognition by MRP1: the γ-glutamyl-cysteine peptide bond is important for binding, whereas the cysteinyl-glycine amide does not seem essential. When the γ-glutamyl-cysteine peptide bond (C-CO-N) is replaced by a urethane isostere (O-CO-N), an effective competitive MRP1-inhibitor (Ki = 11 μM) is obtained. After esterification of this compound to improve its cellular uptake, it inhibited MRP1-mediated efflux of calcein from 2008 ovarian carcinoma cells overexpressing MRP1. This compound also partially reversed the resistance of these cells to methotrexate. Because the urethane isostere is stable toward γ-glutamyl transpeptidase-mediated breakdown, it is an interesting lead-compound for the development of in vivo active MRP1 inhibitors.
    Keywords:
    Efflux
    Conjugate
    Tripeptide
    Isostere
    Topics:
    Drug Transport and Resistance Mechanisms
    HIV/AIDS drug development and treatment
    Amino Acid Enzymes and Metabolism
    Cysteinoyl‐ and Cysteine‐containing Dipeptidoylbenzotriazoles with Free Sulfhydryl Groups: Easy Access to N‐terminal and Internal Cysteine Peptides
    Chemical Biology & Drug Design (2011)
    Tarek S. IbrahimSrinivasa R. TalaSaid A. El‐FekyZakaria K. Abdel‐SamiiAlan R. Katritzky
    N-Protected cysteines 4a-c each with a free sulfhydryl group were prepared in 70-75% yields by treatment of L-cysteine with 1-(benzyloxycarbonyl) benzotriazole (Cbz-Bt) 1a, N-(tert-butyloxy-carbonyl)benzotriazole (Boc-Bt) 1b, and 1-(9-fluorenylmethoxy-carbonyl)benzotriazole (Fmoc-Bt) 1c, respectively. N-Protected, free sulfhydryl cysteines 4a-c were then converted into the corresponding N-protected, free sulfhydryl cysteinoylbenzotriazoles 7a-c (70-85%), which on treatment with diverse amino acids and dipeptides afforded the corresponding N-protected, free sulfhydryl N-terminal cysteine dipeptides 8a-e and tripeptides 8f-h in 73-80% yields. N-Protected, free sulfhydryl cysteine-containing dipeptides 9a,b were converted into the corresponding N-protected, free sulfhydryl dipeptidoylbenzotriazoles 10a,b (69-81%), which on treatment with amino acids, dipeptides, and a tripeptide afforded internal cysteine tripeptides 11a-c, tetrapeptides 11d,e and pentapeptide 11f, each containing a N-protected, free sulfhydryl groups in 70-90% yields under mild conditions. Treatment of N-protected, free sulfhydryl cysteinoylbenzotriazole 7a with diamines 12a,b afforded directly the cysteine-containing disulfide-bridged cyclic peptides 14a,b in 50% yields.
    Amino terminal
    Cysteine Metabolism
    Citations (4)
    History of N-Acetylcysteine
    Springer eBooks (2018)
    Leonore A. Herzenberg
    Tripeptide
    Citations (2)
    Copper Tripeptides
    Springer eBooks (2022)
    Konstantinos Anastassakis
    Tripeptide
    Matrix (chemical analysis)
    Citations (0)
    Novel sources of cysteine conjugate β-lyase for the study of halogenated cysteine conjugate toxicity.
    Adcock Hj
    Conjugate
    Citations (0)
    First application of the Dakin-West reaction to fmoc chemistry: Synthesis of the ketomethylene tripeptide fmoc-Nα-Asp(tBu)-(R,S Tyr(tBu)Ψ(CO-CH2)Gly-OH
    Tetrahedron Letters (1995)
    J. Richard CasimirCéline TurettaLaurent EttouatiJoëlle Paris
    Tripeptide
    Isostere
    Oligopeptide
    Citations (77)
    KNI-102, a novel tripeptide HIV protease inhibitor containing allophenylnorstatine as a transition-state mimic.
    Chemical and Pharmaceutical Bulletin (1991)
    Tsutomu MimotoJunta ImaiSenku TanakaNaoko HattoriSumitsugu Kisanuki
    HIV-1 protease inhibitors containing allophenylnorstatine[Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenyl-butyric acid]-Pro (syn diastereomer) as a transition-state mimic were established to be potent and highly selective. Z-Asn-Apns-Pro-NHBut (KNI-102) is the only tripeptide exhibiting substantial anti-HIV activity and may be of minimum size for potent, selective inhibition of HIV protease. Ready availability due to its simple chemical strucuture and stability should make it valuable for studies of the development of metabolically stable anti-AIDS drugs.
    Tripeptide
    Diastereomer
    Protease inhibitor (pharmacology)
    Oligopeptide
    Citations (80)
    α-Ketoamide Phe—Pro isostere as a new core structure for the inhibition of HIV protease
    Bioorganic & Medicinal Chemistry (1994)
    Benito MuñozChou‐Zen GiamChi‐Huey Wong
    Isostere
    Amide
    Peptide bond
    Citations (26)
    Renin inhibitors based on dipeptide analogs. Incorporation of the hydroxyethylene isostere at the P2/P3 sites
    Journal of Medicinal Chemistry (1990)
    Dale J. KempfEd de LaraHerman H. SteinJerome CohenDavid A. Egan
    The synthesis of a series of renin inhibitors in which the P2 and P3 amino acids are replaced with the hydroxyethylene dipeptide isostere is reported. In vitro evaluation of the inhibitors has revealed that this isostere is an acceptable amide-bond replacement in which activity is maintained and stability is enhanced. Structure-activity relationships of this series resemble but do not parallel those of the corresponding dipeptide-containing inhibitors.
    Isostere
    Amide
    Citations (16)
    Mechanisms of Cysteine S ‐conjugate β‐Lyases
    Advances in enzymology and related areas of molecular biology/Advances in enzymology and related subjects (1998)
    Arthur J. L. Cooper
    Mercapturic acids are conjugates of S-(N-acetyl)-L-cysteine formed during the detoxification of xenobiotics and during the metabolism of such endogenous agents as estrogens and leukotrienes. Many mercaturates are formed from the corresponding glutathione S-conjugates. This chapter focuses on (a) the discovery of the cysteine S-conjugate beta-lyases; (b) the involvement of pyridoxal-5-phosphate; (c) the influence of the electron-withdrawing properties of the group attached to the sulfur atom; and (d) the potential of cysteine S-conjugates as pro-drugs.
    Conjugate
    Citations (39)
    Kynostatin (KNI-227 and -272, highly potent anti-HIV agents: conformationally constrained tripeptide inhibitors of HIV protease containing allophenylnorstatine.
    Chemical and Pharmaceutical Bulletin (1992)
    Tsutomu MimotoJunya ImaiSumitsugu KisanukiHiroshi EnomotoNaoko Hattori
    Selective and potent HIV protease inhibitors containing allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition-state mimic were designed and synthesized. Among them, conformationally constrained tripeptide derivatives, kynostatin (KNI)-227 and -272 (Fig. 1), exhibited highly potent antiviral activities against a wide spectrum of HIV isolates. Ready availability due to the simple synthetic procedure and the excellent antiviral properties indicate that KNI-227 and KNI-272 are promising candidates as selective anti-AIDS drugs.
    Tripeptide
    Isostere
    Protease inhibitor (pharmacology)
    Oligopeptide
    Citations (146)