- Synthesis, antiproliferative activity, and DNA binding studies of nucleoamino acid-containing Pt(II) complexes
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We here report our studies on the reaction with the platinum(II) ion of a nucleoamino acid constituted by the l-2,3-diaminopropanoic acid linked to the thymine nucleobase through a methylenecarbonyl linker. The obtained new platinum complexes, characterized by spectroscopic and mass spectrometric techniques, were envisaged to exploit synergistic effects due to the presence of both the platinum center and the nucleoamino acid moiety. The latter can be potentially useful to protect the complexes from early deactivation, as well as to facilitate their cell internalization. The biological activity of the complexes in terms of antiproliferative effects was evaluated in vitro on different cancer cell lines and healthy cells, showing the best results on human cervical adenocarcinoma (HeLa) cells along with good selectivity for cancer over normal cells. In contrast, the metal-free nucleoamino acid did not show any cytotoxicity on both normal and cancer cell lines. Finally, the ability of the novel Pt(II) complexes to bind various DNA model systems was investigated by circular dichroism (CD) spectroscopy and polyacrylamide gel electrophoresis analyses proving that the newly obtained compounds can potentially target DNA, similarly to other well-known anticancer Pt complexes, with a peculiar G-quadruplex vs. duplex selectivity.
- Capasso, Domenica,Coppola, Angela,Di Gaetano, Sonia,Montesarchio, Daniela,Musumeci, Domenica,Platella, Chiara,Riccardi, Claudia,Roviello, Giovanni N.
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- Orthogonal chemistry for the synthesis of thiocoraline-triostin hybrids. Exploring their structure-activity relationship
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The natural compounds triostin and thiocoraline are potent antitumor agents that act as DNA bisintercalators. From a pharmaceutical point of view, these compounds are highly attractive although they present a low pharmacokinetic profile, in part due to their low solubility. Synthetically, they represent a tour de force because no robust strategies have been developed to access a broad range of these bicyclic (depsi)peptides in a straightforward manner. Here we describe solid-phase strategies to synthesize new bisintercalators, such as thiocoraline-triostin hybrids, as well as analogues bearing soluble tags. Orthogonal protection schemes (up to five from: Fmoc, Boc Alloc, pNZ, o-NBS, and Troc), together with the right concourse of the coupling reagents (HOSu, HOBt, HOAt, Oxyma, EDC, DIPCDI, PyAOP, PyBOP, HATU, COMU), were crucial to establish the synthetic plan. In vitro studies and structure-activity relationships have been shown trends in the structure-activity relationship that will facilitate the design of new bisintercalators.
- Tulla-Puche, Judit,Auriemma, Sara,Falciani, Chiara,Albericio, Fernando
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- Rearrangement of Nα-Protected L-Asparagines with Iodosobenzene Diacetate. A Practical Route to β-Amino-L-alanine Derivatives
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A general synthetic method for the Hofmann rearrangement of protected asparagines has been developed. Reaction of asparagine derivatives with iodosobenzene diacetate (PIDA) in mixed solvents produces β-amino-L-alanines in good yield. Advantages over the commonly used reagent bis(trifluoroacetoxy)iodobenzene have been discussed.
- Zhang, Lin-Hua,Kauffman, Goss S.,Pesti, Jaan A.,Yin, Jianguo
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- Copper-Free Solid-Phase Synthesis of Triazolo[1,5-a][1,4]diazepin-6-ones
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Synthesis of triazolo[1,5-a][1,4]diazepin-6-ones on solid support is reported in this article. Amino acids immobilized on Wang resin were nosylated and alkylated with propargyl alcohol, but-2-yn-1-ol or different 3-phenylprop-2-yn-1-ols using Mitsunobu alkylation conditions. After denosylation, acylation with Fmoc-azidoalanine yielded linear precursors that were thermally cyclized on resin to give immobilized triazolodiazepinones. After cleavage from the polymer support, the target compounds were obtained in high crude purities and good overall yields. Furthermore, the synthetic approach was applied to convenient solid-phase synthesis of oligopeptide containing the triazolodiazepinone moiety as the peptidomimetic heterocyclic constraint. (Figure presented.).
- Kriegelsteinová, Patricia,Lemrová, Barbora,Ru?ilová, Veronika,Soural, Miroslav
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p. 1112 - 1119
(2021/01/04)
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- Chemo-selective Rh-catalysed hydrogenation of azides into amines
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Rh/Al2O3 can be used as an effective chemo-selective reductive catalyst that combines the mild conditions of catalytic hydrogenation with high selectivity for azide moieties in the presence of other hydrogenolysis labile groups such as benzyl and benzyloxycarbonyl functionalities. The practicality of this strategy is exemplified with a range of azide-containing carbohydrate and amino acid derivatives.
- Galan, M. Carmen,Ghirardello, Mattia,Ledru, Helene,Sau, Abhijit
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supporting information
(2020/02/18)
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- Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine inhibitors toward butyrylcholinesterase in Alzheimer's disease
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Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.
- de Andrade, Peterson,Mantoani, Susimaire P.,Gon?alves Nunes, Paulo Sérgio,Magadán, Carlos Roca,Pérez, Concepción,Xavier, Danilo Jord?o,Hojo, Elza Tiemi Sakamoto,Campillo, Nuria E.,Martínez, Ana,Carvalho, Ivone
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p. 931 - 943
(2019/02/14)
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- Modified Peptide Inhibitors of the Keap1–Nrf2 Protein–Protein Interaction Incorporating Unnatural Amino Acids
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Noncovalent inhibitors of the Keap1–Nrf2 protein–protein interaction (PPI) have therapeutic potential in a range of disease states including neurodegenerative diseases (Parkinson's and Alzheimer's diseases), chronic obstructive pulmonary disease and various inflammatory conditions. By stalling Keap1-mediated ubiquitination of Nrf2, such compounds can enhance Nrf2 transcriptional activity and activate the expression of a range of genes with antioxidant response elements in their promoter regions. Keap1 inhibitors based on peptide and small-molecule templates have been identified. In this paper we develop the structure–activity relationships of the peptide series and identify a group of ligands incorporating unnatural amino acids that demonstrate improved binding affinity in fluorescence polarisation, differential scanning fluorimetry and isothermal titration calorimetry assays. These modified peptides have the potential for further development into peptidomimetic chemical probes to explore the role of Nrf2 in disease and as potential lead structures for drug development.
- Georgakopoulos, Nikolaos D.,Talapatra, Sandeep K.,Gatliff, Jemma,Kozielski, Frank,Wells, Geoff
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p. 1810 - 1816
(2018/08/06)
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- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
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The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
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p. 202 - 214
(2017/04/06)
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- Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer
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There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor
- Wiedmann, Mareike M.,Tan, Yaw Sing,Wu, Yuteng,Aibara, Shintaro,Xu, Wenshu,Sore, Hannah F.,Verma, Chandra S.,Itzhaki, Laura,Stewart, Murray,Brenton, James D.,Spring, David R.
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supporting information
p. 524 - 529
(2017/01/07)
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- Strategy for "Detoxification" of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2
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The histone methyltransferase PRC2 plays a central role in genomic stability and cellular development. Consequently, its misregulation has been implicated in several cancers. Recent work has shown that a histone H3 mutant, where the PRC2 substrate residue Lys27 is replaced by methionine, is also associated with cancer phenotypes and functions as an inhibitor of PRC2. Here we investigate the mechanism of this PRC2 inhibition through kinetic studies and photo-cross-linking. Efficient inhibition is dependent on (1) hydrophobic lysine isosteres blocking the active site, (2) proximal residues, and (3) the H3 tail forming extensive contacts with the EZH2 subunit of PRC2. We further show that naturally occurring post-translational modifications of the same H3 tail, both proximal and distal to K27M, can greatly diminish the inhibition of PRC2. These results suggest that this potent gain of function mutation may be "detoxified by modulating alternate chromatin modification pathways.
- Brown, Zachary Z.,Müller, Manuel M.,Jain, Siddhant U.,Allis, C. David,Lewis, Peter W.,Muir, Tom W.
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supporting information
p. 13498 - 13501
(2015/02/02)
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- Clickable coumarins as fluorescent labels for amino acids
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Seven trifunctional conjugates of Fmoc-protected amino acids with alkynyloxy-substituted coumarins have been prepared and spectroscopically characterized. The coumarin core was either coupled to the α or side chain amino group. This design allows for the
- Mertens, Matthias D.,Gütschow, Michael
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p. 2191 - 2200
(2014/08/18)
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- Efficient synthesis of Fmoc-protected azido amino acids
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The efficient two-step synthesis of Fmoc-protected L-azidoalanine and L-azidohomoalanine from readily available Fmoc-protected asparagine and glutamine, respectively, is reported. The synthetic route proceeds in good yield, requires no extra purification steps, and can be carried out on gram scale. The resulting azido amino acids are of sufficient purity for solid-phase peptide synthesis, as demonstrated in the synthesis of a model pentapeptide. Georg Thieme Verlag Stuttgart New York.
- Lau, Yu Heng,Spring, David R.
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experimental part
p. 1917 - 1919
(2011/10/01)
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- Mapping the landscape of potentially primordial informational oligomers: Oligo-dipeptides tagged with orotic acid derivatives as recognition elements
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Partner up! Base-pairing properties of oligo-dipeptides tagged with orotic acid and its 2,4- diamino counterpart (see structure) are found to be consistent with previously observed correlations between ΔpKa values and the pairing strength of co
- Zhang, Xuejun,Krishnamurthy, Ramanarayanan
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supporting information; experimental part
p. 8124 - 8128
(2010/03/01)
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- Synthesis of thiourea-tethered C-glycosyl amino acids via isothiocyanate-amine coupling
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A new class of C-glycosyl amino acids displaying a thiourea segment as a linker has been designed and synthesized by addition of peracetylated glycosylmethyl isothiocyanates to an amine-functionalized amino acid (N α-Fmoc-β-amino-l-alanine). Th
- Barghash, Reham F.,Massi, Alessandro,Dondoni, Alessandro
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body text
p. 3319 - 3330
(2009/10/23)
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- Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line
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The epothilones, a family of macrolactone natural products produced by the myxobacterial species Sorangium cellulosum, are of current clinical interest as antitumor agents. Inspection of the structure of the epothilones suggests a hybrid polyketide/nonribosomal peptide biosynthetic origin, and the recent sequencing of the epothilone biosynthetic gene cluster has validated this proposal. Here we have examined unnatural substrates with the first two enzymes of the biosynthetic pathway, EpoA and EpoB, to investigate the enzymatic construction of alternate heterocyclic structures and the subsequent elongation of these products by the third enzyme of the pathway, EpoC. The epothilone biosynthetic machinery can utilize serine to install an oxazole in place of a thiazole in the epothilone structure and will tolerate functionalized donor groups from the EpoA-ACP domain to produce epothilone fragments modified at the C21 position. These studies with the early enzymes of the epothilone biosynthesis cluster suggest that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit. Copyright
- Schneider, Tanya L.,Walsh, Christopher T.,O'Connor, Sarah E.
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p. 11272 - 11273
(2007/10/03)
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- Diaminopropionic acid derivatives
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A compound of formula 1a which is useful for treating reperfusion injury, and salts, prodrugs, and related compounds.
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- Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent
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The synthesis of MEN11420, a potent tachykinin receptor antagonist, has been achieved. The bicyclic glycosylated structure of MEN11420 was constructed via intramolecular double cyclization using CIP-mediated activation. The head to tail cyclization of the linear precursor, which contained an α-amino acid at its C-terminus, proceeded so rapidly that no serious racemization was apparent at the activated carboxyl function. The desired product was obtained without the need for purification of the intermediates throughout the synthesis.
- Akaji, Kenichi,Aimoto, Saburou
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p. 1749 - 1755
(2007/10/03)
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- Synthesis of the first tricyclic homodetic peptide. Use of coordinated orthogonal deprotection to achieve directed ring closure
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The discovery of somatostatin antagonists at one or more receptor subtypes remains an important goal. We therefore undertook the synthesis of the homodetic tricyclic peptide (1) hoping to cause conformational distortion and thereby achieve this biological goal. The synthetic strategy called for five dimensional orthogonal amino protection. The carboxyl and amino protecting groups were selected to assure the desired selective ring closures. The amino protecting groups were also chosen to permit differentiation between the two lysine ε-amino groups. An improved general cyclization procedure was achieved, which provided the complex c-octapeptide 13 in 93% yield. Biological assay results for 1 are also presented.
- Hirschmann, Ralph,Yao, Wenqing,Arison, Byron,Maechler, Laurie,Rosegay, Avery,Sprengeler, Paul A.,Smith III, Amos B.
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p. 7179 - 7202
(2007/10/03)
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