- Orthogonally protected artificial amino acid as tripod ligand for automated peptide synthesis and labeling with [99mTc(OH2) 3(CO)3]+
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1,2-Diamino-propionic acid (Dap) is a very strong chelator for the [ 99mTc(CO)3]+ core, yielding small and hydrophilic complexes. We prepared the lysine based Dap derivative l-Lys(Dap) in which the ε-NH2 group was replaced by the tripod through conjugation to its α-carbon. The synthetic strategy produced an orthogonally protected bifunctional chelator (BFC). The -NH2 group of the α-amino acid portion is Fmoc- and the -NH2 of Dap are Boc-protected. Fmoc-l-Lys(Dap(Boc)) was either conjugated to the N- and C-terminus of bombesin BBN(7-14) or integrated into the sequence using solid-phase peptide synthesis (SPPS). We also replaced the native lysine in a cyclic RGD peptide with l-Lys(Dap). For all peptides, quantitative labeling with the [99mTc(CO)3]+ core at a 10 μM concentration in PBS buffer (pH = 7.4) was achieved. For comparison, the rhenium homologues were prepared from [Re(OH2)3(CO) 3]+ and Lys(Dap)-BBN(7-14) or cyclo-(RGDyK(Dap)), respectively. Determination of integrin receptor binding showed low to medium nanomolar affinities for various receptor subtypes. The IC50 of cyclo-(RGDyK(Dap[Re(CO)3])) for αvβ3 is 7.1 nM as compared to 3.1 nM for nonligated RGD derivative. Biodistribution studies in M21 melanoma bearing nude mice showed reasonable α vβ3-integrin specific tumor uptake. Altogether, orthogonally protected l-Lys(Dap) represents a highly versatile building block for integration in any peptide sequence. Lys(Dap)-precursors allow high-yield 99mTc-labeling with [99mTc(OH2) 3(CO)3]+, forming small and hydrophilic complexes, which in turn leads to peptide radiopharmaceuticals with excellent in vivo characteristics.
- Shen, Yunjun,Schottelius, Margret,Zelenka, Karel,De Simone, Mariarosaria,Pohle, Karolin,Kessler, Horst,Wester, Hans-Jürgen,Schmutz, Paul,Alberto, Roger
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- Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity
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Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
- Schmitt, Martin L.,Hauser, Alexander-Thomas,Carlino, Luca,Pippel, Martin,Schulz-Fincke, Johannes,Metzger, Eric,Willmann, Dominica,Yiu, Teresa,Barton, Michelle,Schüle, Roland,Sippl, Wolfgang,Jung, Manfred
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p. 7334 - 7342
(2013/10/21)
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- Synthesis of (S)-gizzerosine, a potent inducer of gizzard erosion in chicks
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(S)-Gizzerosine, a potent inducer of gizzard erosion in chicks, was synthesized using successive zinc-mediated and palladium-catalyzed coupling reactions as the key steps.
- Shimasaki, Yasuharu,Kiyota, Hiromasa,Sato, Minoru,Kuwahara, Shigefumi
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p. 9628 - 9634
(2007/10/03)
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- Facile synthesis of (S)-gizzerosine - A potent inducer of gizzard erosion in chicks - Using successive zinc-mediated and palladium-catalyzed coupling reactions
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Gizzerosine, a potent inducer of gizzard erosion in chicks, was synthesized using successive inc-mediated and palladium-catalyzed coupling reactions as the key steps. The piperonyl moiety was used as a novel N-protecting group. Georg Thieme Verlag Stuttga
- Shimasaki, Yasuharu,Kiyota, Hiromasa,Sato, Minoru,Kuwahara, Shigefumi
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p. 3191 - 3192
(2007/10/03)
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- INDOLES, BENZIMIDAZOLES OR NAPHHIMIDAZOLES AS HISZONE DEACETYLASE (HDAC) INHIBITOR
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A compound of the following formula (I):whereinR?1? is acyl, R?2? is hydrogen, orR?1? and R?2? are linked together to form a heterocyclic ring, R?5? is hydroxy, hydroxylamino, lower alkyl, lower alkoxy, halo(lower)alkyl or hydroxy(lower)alkyl, Q is lower
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- SYNTHESIS OF N-BENZYLOXYCARBONYL-L-α-AMINOADIPIC ACID, α-BENZYL ESTER
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A new synthesis of N-benzyloxycarbonyl-L-α-aminoadipic acid, α-benzyl ester (1) from L-lysine monohydrochloride (2) is reported.
- Baldwin, Jack E.,Killin, Stephen J.,Adlington, Robert M.,Spiegel, Udo
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p. 2633 - 2636
(2007/10/02)
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- SYNTHESIS OF THE RACEMIC AND OPTICALLY ACTIVE FORMS OF GIZZEROSINE, THE INDUCER OF GIZZARD EROSION IN CHICKS
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The racemate end both the (R)- and (S)-forms of gizzerosine were synthesised, and the (S)-isomer was identified as the toxic substance in fish meal causing severe gizzard erosion (black vomit) in chicks.
- Mori, Kenji,Sugai, Takeshi,Maeda, Yukari,Okazaki, Tomomi,Noguchi, Tadashi,Naito, Hiroshi
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p. 5307 - 5312
(2007/10/02)
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- Chemistry of Naturally Occurring Polyamines. 7. Selective Functionalization of Hydroxyputrescine
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As part of a program to synthesize biologically interesting polyamines and their conjugates, we report studies on the structure and reactivity of hydroxyputrescine-aldehyde adducts which permit regioselective functionalization of this rather rare naturall
- Tice, Colin M.,Ganem, Bruce
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p. 5043 - 5048
(2007/10/02)
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- Direct Preparation of α>-Diprotected L-α-Aminoadipic Acid from L-Lysine
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L-Lysine was converted into N-benzyloxycarbonyl-L-α-aminoadipic acid 1-benzyl ester by a short route which avoids the intermediacy of L-α-aminoadipic acid.
- Baldwin, Jack E.,Harrison, Paul,Murphy, John A.
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p. 818 - 819
(2007/10/02)
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