Synthesis of Cross-linkable 2, 5-Diketopiperazine Derivatives (original) (raw)
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Tetrahedron Letters, 1998
Diketopiperazines, which are cyclic dipeptides, are often formed by a side reaction of solid-phase peptide synthesis. Using the new “Backbone Amide Linker,” this chemistry can be conveniently harnessed for the intentional preparation of diketopiperazines. These products will be useful scaffolds for combinatorial chemistry, since they incorporate three different points of diversity: both amino acid side-chains and one (of the two)
Journal of Heterocyclic Chemistry, 2015
Unnatural aromatic amino acids are useful tools in drug discovery, since their insertion in bioactive peptide sequences can change the side chains spatial orientation, the backbone conformation and above all, their bioactivity. In this communication, we propose a straightforward method to synthesize 2′,6′-dimethyl-tyrosine and 2′,6′-dimehylphenyl-alanine derivatives as handling building blocks for peptide synthesis via unsaturated diketopiperazine (DKP) intermediate.
A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues
Tetrahedron, 2008
Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a simple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester derivatives and their intramolecular cyclization. In this method, the key step of the imide formation was accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester 2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields when the same primary amido-esters were treated with the previous base and the intermediate potassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning our pharmacological studies.
The Journal of Organic Chemistry, 2006
1. General Experimental Information: 1 H NMR and 13 C spectra were recorded at 400 MHz and 100.0 MHz respectively at ambient temperature with CDCl 3 as solvent unless otherwise stated. Chemical shifts are reported in parts per million relative to CDCl 3 (1 H, δ 7.26; 13 C, δ 77.0). Data are reported as follows: chemical shift, multiplicity (overlp=overlapping, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant, and integration. All 13 C NMR spectra were recorded with complete proton decoupling. Optical rotations were recorded at 589 nm, and are reported as [α] D 20 (concentration in grams/100 mL solvent). Analytical and preparative HPLC were performed with a mass spectrometer, diode array, and a ELS detector. An Xterra 4.6 x 30 mm RP 8 column was used for analytical HPLC and an Xterra 19 x 50 mm RP 18 column was used for preparative HPLC. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-A plates. Methylene chloride, THF and toluene were purified by passing through two packed columns of neutral alumina. Microwave reactions were performed using the Discover™ Explorer System. 2. Sc(OTf) 3-Catalyzed Aza-annulation Reactions. (2S,5S,6S)-methyl 6-(4-bromophenyl)-1-(2,2,2-trifluoroacetyl)-1,2,5,6-tetrahydro-5methylpyridine-2-carboxylate (trans-8a): This compound was synthesized using general procedure 1 described in the Experimental Section of the paper. Yield 81%. Colorless oil; [α] D 20-82.0 o (c = 0.2, CHCl 3); IR (thin film) ν
The synthesis of alternative diketopiperazines as potential RGD mimetics
Journal of Peptide Science, 2006
Alternative RGD mimetics -with the exception of glycine -c(Arg-Asp) 1, c(Arg-Glu) 2 and c[Arg-Asp(Phe-OH)] 3 were synthesized. The DKPs were prepared on solid phase with orthogonal protection allowing further derivatization in solution. During solution phase cyclization in NH 3 /methanol, the side chain benzyl ester group of H-Arg(Tos)-Asp(OBzl)-OMe and H-Arg(Tos)-Glu(OBzl)-OMe suffer transesterification, while β-t-butyl or β-cyclohexyl esters are stable under the same conditions. In spite of the simple structure, all compounds bind selectively to the α v β 3 integrin receptor, 3 showing the highest affinity with an IC 50 value of 0.74 µM value. On the other hand only 3 binds with measurable activity to the α IIb β 3 receptor (IC 50 159 µM). The binding affinities seem to be in accordance with the distances between the arginine guanidino and the aspartic acid carboxyl group in extended conformation determined by semiempirical geometry optimization. Molecular geometry optimizations were performed in the case of c(Arg-Asp), c(Arg-Glu) and c[Arg-Asp(Phe-OH)] at RAM1 level of theory using Gaussian03 [4]. The highest possible fixed distance values were used for each peptide. c[Arg(Tos)-Glu(OMe)]. 1 H NMR: δ 8.16 (2H, s, lactam NHs), 7.62 and 7.28 (2x2H, d, J = 7.2 Hz, ArHs in Tos), 7.03, 6.73 and 6.56 (3x1H, 3xbr s, guanidino NHs), 3.86 [1H, t, J = 5.1 Hz, α-CH (Glu)], 3.80 [1H, t, J = 4.8 Hz, α-CH (Arg)], Figure 4 Inhibition of binding of fibronectin to isolated α IIb β 3 integrin receptor with c(Arg-Asp); c(Arg-Glu) and c[Arg-Asp(Phe-OH)] IC 50 159 µM.
Synthesis and biological evaluation of a post-synthetically modified Trp-based diketopiperazine
MedChemComm, 2013
A series of C2-arylated analogues of the diketopiperazine brevianamide F has been synthesized using a mild Pd-catalyzed CH-activation procedure. Biological evaluation of the new derivatives in different cell lines shows that this modification is responsible for the remarkable change in activity, turning a mild antibiotic and antifungal natural product (brevianamide F) into novel antitumoral compounds. Furthermore, the approach stated represents a new straightforward and versatile methodology with promising applications in peptidomimetics and medicinal chemistry.