- RETRACTED ARTICLE: Synthesis and bioevaluation of aryl-guanidino polyamine conjugates targeting the polyamine transporter
-
Aryl-guanidino polyamine conjugates were prepared to evaluate their recognition for polyamine transporter (PAT) via a-difluoromethylornithine (DFMO) and spermidine (SPD)-treated B16 cell lines. The potent synergistic effects of DFMO on guanidino polyamine conjugates indicated that the presence of DFMO strongly facilitates the transport of conjugates into cells via PAT on cell membrane. The apoptotic mechanisms of triamine conjugates 10 and 1 (with and without guanidine groups) revealed that they induced apoptosis of Hela cells through the mitochondrial pathway associated with lysosomes, while DFMO strongly synergizes the function of 10 without changing the apoptotic route. Taken together, guanidino polyamine conjugates can target PAT for transport as normal polyamine ones, and the presence of guanidine in the polyamine vectors does not seem to alter the cellular targets of the conjugates, which may depend mainly on the pharmacophore.
- Wang, Jianhong,Chen, Zhiyong,Xie, Songqiang,Zhao, Jin,Wang, Chaojie
-
-
Read Online
- Tailoring the Physicochemical Properties of Antimicrobial Peptides onto a Thiazole-Based γ-Peptide Foldamer
-
Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-based γ-peptide oligomers named ATCs as tunable scaffolds to design polycationic AMP mimetics. Knowing the side chain distribution along the backbone, we rationally designed facially amphiphilic sequences with bactericidal effect in the micromolar range. Since no hemolytic activity was detected up to 100 μM, this class of compounds has shown the potential for therapeutic development.
- Bonnel, Clément,Legrand, Baptiste,Simon, Matthieu,Clavié, Margaux,Masnou, Agnès,Jumas-Bilak, Estelle,Kang, Young Kee,Licznar-Fajardo, Patricia,Maillard, Ludovic T.,Masurier, Nicolas
-
-
Read Online
- MODIFIED PEPTIDES AND THEIR USE
-
The invention relates to a compound of formula (A) wherein n is an integer from 1 to 6, and R1, R1', R2, R2', R3, R3' are cationic or hydrophobic residues.
- -
-
Paragraph 0081; 0084; 0104; 0108
(2020/05/13)
-
- N,N,N-Tris(tert-butoxycarbonyl)-l-arginine: five isoforms whose obtainment depends on procedure and scrupulous NMR confirmation of their structures
-
l-arginine is often covalently linked to vectors for gene or drug delivery as a means of increasing their transfection activity and reducing toxicity. This strategy relies on the protection of basic nitrogen atoms, for example, by employing the tert-butoxycarbonyl group. Our aim in the present work was to prepare the widely described αN,ωN,ω′N-tris(tert-butyloxycarbonyl)-l-arginine as a single isomer in high yield and with high levels of purity for use in the esterification of dendrimers with several peripheral hydroxyl groups. Following three reported protocols which assured this goal, we observed the unexpected formation of four additional isomers. Using the first procedure, αN,ωN,ω′N-tris(tert-butyloxycarbonyl)-l-arginine was never obtained. The second procedure delivered the desired compound as a mixture of geometric isomers (E/Z), while the third protocol led to a single isomer in high yield and purity, but with an unreported symmetrical structure. Since Boc protection is transient, this discovery would seem to be of little interest, but preliminary results from an ongoing investigation of the behavior of each of the isomers obtained in the esterification reactions of interest has shown that their reactivity depends on their structure. Although this research is ongoing, here we report a detailed description of these unexpected results, along with an NMR investigation focusing on the double-bond geometry and position which enabled confirmation of the structures.
- Alfei, Silvana,Castellaro, Sara
-
p. 1811 - 1832
(2017/12/04)
-
- Stable peptide-based PACE4 inhibitors
-
It is provided PACE4 inhibitors and their uses for treating infection, cancer. Particularly, it is provided a method or use for the treatment of a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the PACE4 inhibitors or the composition disclosed.
- -
-
Page/Page column 31; 32
(2017/12/27)
-
- ANTIBACTERIAL THERAPEUTICS AND PROPHYLACTICS
-
The present disclosure relates generally to novel molecules, compositions, and formulations for treatment of bacterial infections in general and more specifically to bacterial infections with antibiotic resistant pathogens.
- -
-
Paragraph 00337; 00375
(2017/02/24)
-
- Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation
-
The preparation of peptide fragments containing dehydrovaline and dehydroisoleucine moieties present in the antibiotic myxovalargin is reported. Peptide formation is based on a copper-mediated C-N cross-coupling protocol between an acyl amide and a peptidic vinyl iodide. The presence of a neighboring arginine in the vinyl iodide posed a challenge with respect to the choice of the protecting group and the reaction conditions. It was found that ornithine - a suitable precursor - is better suited than arginine for achieving good yields for the C-N cross-coupling reaction. The optimized conditions were utilized for the synthesis of peptides 32, 33, 39 and 40 containing a neighboring ornithine as well as for the tripeptide 44 containing dehydroisoleucine with the correct stereochemistry.
- Gille, Franziska,Kirschning, Andreas
-
supporting information
p. 564 - 570
(2016/04/08)
-
- LYSINE OLIGOMER DERIVATIVE AND CARTILAGE TISSUE MARKER MADE THEREOF
-
There is provided a lysine oligomer derivative, wherein an ε-amino group and a carboxyl group of lysines are linked via a peptide bond, and a group capable of generating or absorbing electromagnetic wave is bonded to a C-terminal carboxyl group, an N-terminal amino group and/or an α-amino group. This lysine oligomer derivative has the characteristic of specifically accumulating in the cartilage matrix and can generate or absorb an electromagnetic wave, and is, therefore, useful as a cartilage tissue marker.
- -
-
Paragraph 0104; 0105
(2015/03/28)
-
- Enantioselective diamination with novel chiral hypervalent iodine catalysts
-
Vicinal diamines constitute one the most important functional motif in organic chemistry because of its wide occurrence in a variety of biological and pharmaceutical molecules. We report an efficient metal-free, highly stereoselective intramolecular diamination using a novel chiral hypervalent iodine reagent together with its application as an efficient catalyst for the synthesis of diamines.
- Mizar, Pushpak,Laverny, Aragorn,El-Sherbini, Mohammad,Farid, Umar,Brown, Michael,Malmedy, Florence,Wirth, Thomas
-
supporting information
p. 9910 - 9913
(2014/08/18)
-
- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
-
3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Schweifer, Anna,Kvaternik, Herbert,Aigner, Reingard M.,Mereiter, Kurt
-
p. 3387 - 3391,5
(2012/12/12)
-
- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
-
3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Kvaternik, Herbert,Schweifer, Anna,Mereiter, Kurt,Aigner, Reingard M.
-
p. 3387 - 3391
(2013/01/15)
-
- On the role of flexibility in protein-ligand interactions: The example of p53 tetramerization domain
-
The recognition of protein surfaces by designed ligands has become an attractive approach in drug discovery. However, the variable nature and irregular behavior of protein surfaces defy this new area of research. The easy to understand "lock-and-key" model is far from being the ideal paradigm in biomolecular interactions and, hence, any new finding on how proteins and ligands behave in recognition events paves a step of the way. Herein, we illustrate a clear example on how an increase in flexibility of both protein and ligand can result in an increase in the stability of the macromolecular complex. The biophysical study of the interaction between a designed flexible tetraguanidinium-calix[4]arene and the tetramerization domain of protein p53 (p53TD) and its natural mutant p53TD-R337H shows how the floppy mutant domain interacts more tightly with the ligand than the well-packed wild-type protein. Moreover, the flexible calixarene ligand interacts with higher affinity to both wild-type and mutated protein domains than a conformationally rigid calixarene analog previously reported. These findings underscore the crucial role of flexibility in molecular recognition processes, for both small ligands and large biomolecular surfaces. Copyright
- Gordo, Susana,Martos, Vera,Vilaseca, Marta,Menendez, Margarita,De Mendoza, Javier,Giralt, Ernest
-
supporting information
p. 1463 - 1469
(2013/01/11)
-
- Aza-β3-amino acid containing peptidomimetics as cAMP-dependent protein kinase substrates
-
Peptidomimetic analogs of the peptide RRASVA, known as the "minimal substrate" of the catalytic subunit of the cAMP-dependent protein kinase (PKA), were synthesized by consecutive replacement of natural amino acids by their aza-β3 analogs. The peptidomimetics were tested as PKA substrates and the kinetic parameters of the phosphorylation reaction were determined. It was found that the interaction of these peptidomimetics with the enzyme active center was sensitive to the location of the backbone modification, while the maximal rate of the reaction was practically not affected by the structure of substrates. The pattern of molecular recognition of peptidomimetics was in agreement with the results of structure modeling and also with the results of computational docking study of peptide and peptidomimetic substrates with the active center of PKA. It was concluded that the specificity determining factors which govern substrate recognition by the enzyme should be grouped along the phosphorylatable substrate, and such clustering might open new perspectives for pharmacophore design of peptides and peptide-like ligands.
- Kisseljova, Ksenija,Kuznetsov, Aleksei,Baudy-Floc'H, Michle,Jaerv, Jaak
-
supporting information; experimental part
p. 229 - 233
(2010/10/01)
-
- Process for the preparation of substituted pyrimidine derivatives
-
The present invention is directed to processes for the preparation of substituted pyrimidine derivatives, useful as intermediates in the synthesis of histamine H4 receptor modulators, and to intermediates in H4 modulator synthesis.
- -
-
Page/Page column 16
(2010/02/16)
-
- INOSITOL-BASED MOLECULAR TRANSPORTERS AND PROCESSES FOR THE PREPARATION THEREOF
-
Inositol derivatives in accordance with the present invention are effective in significantly enhancing the transportation of various therapeutic molecules across a biological membrane, which may include the plasma membrane, nuclear membrane or blood-brain barrier.
- -
-
Page/Page column 19-20
(2008/06/13)
-
- 2H-phthalazin-1-one derivatives and drug containing its derivatives as active ingredient
-
Poly(ADP-ribose)polymerase inhibitors containing as the active ingredient 2H-phthalazin-1-one derivatives represented by general formula (I) (wherein each symbol is as defined in the description) or salts thereof. The compounds of the general formula (I) inhibit poly(ADP-ribose)polymerase and are useful as preventives and/or remedies for various ischemic diseases (brain, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory intestinal diseases, multiple encephalosclerosis, arthritis, etc.), nerve degeneration diseases (extrapyramidal disorder, Alzheimer's disease, muscular dystrophy, etc.), diabetes, shock, head trauma, renal insufficiency, hyperalgesia, etc. These compounds are also useful as sensitizers for agents against retroviruses (HIV, etc.) and chemotherapy for cancer.
- -
-
Page/Page column 230; 231
(2010/11/30)
-
- PYRAZOLO-QUINAZOLINE DERIVATIVES,PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
-
Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
- -
-
Page 32; 193
(2008/06/13)
-
- Optimisation of the synthesis of guanidines from amines via nitroguanidines using 3,5-dimethyl-N-nitro-1H-pyrazole-1-carboxamidine
-
The synthesis of the useful reagent for the preparation of guanidines, 3,5-dimethyl-N-nitro-1-pyrazole-1-carboxamidine (DMNPC), has been optimised. A detailed protocol for using this reagent for the preparation in pure form of a range of guanidines via nitroguanidines is described. A comparison has been made regarding efficiency between DMNPC and the guanidinylating reagents N,N′-bis-Boc-1-pyrazole-1-carboxamidine (2) and N,N′-bis-Boc- N′-triflylguanidine (3).
- Castillo-Melendez, Joel A.,Golding, Bernard T.
-
p. 1655 - 1663
(2007/10/03)
-
- Preparation and evaluation of a polymer-supported Mukaiyama reagent
-
The synthesis of a polymer-supported Mukaiyama reagent is described. This preparation was thoroughly optimized using a DoE approach to achieve optimum loading, and the procedure was successfully applied to prepare the supported reagent on a 10g scale. This reagent proved to be effective for the formation of carbodiimides through the dehydration of thioureas and for a one-pot guanylation of primary amines.
- Convers, Emmanuelle,Tye, Heather,Whittaker, Mark
-
p. 3401 - 3404
(2007/10/03)
-
- Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: A convenient protocol for the synthesis of highly functionalized guanidines
-
An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.
- Powell, David A.,Ramsden, Philip D.,Batey, Robert A.
-
p. 2300 - 2309
(2007/10/03)
-
- Fused cycloheptane and fused azacycloheptane compounds and their methods of use
-
The invention comprises novel compounds that are effective in the prophylaxis and treatment of diseases, such as integrin receptors mediated diseases, in particular, diseases or conditions mediated by integrin receptors, such as αvβ3, αvβ5, αvβ6and the like. The invention encompasses novel compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of such diseases and disorders. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
- -
-
-
- Triurethane-protected guanidines and triflyldiurethane-protected guanidines: New reagents for guanidinylation reactions
-
New guanidinylation reagents are reported. These reagents consist of N,N',N''-tri-Boc-guanidine (1) and N,N',N''-tri-Cbz-guanidine (2), which allow for the facile conversion of alcohols to substituted guanidines. A series of arginine analogues were synthesized via condensation of a primary or secondary alcohol with the guanidinylation reagents 1 or 2, under Mitsunobu conditions, to produce protected alkylated guanidines. In addition, an extended study of the previously reported reagents N,N'-di-Boc-N''- triflylguanidine (3) and N,N'-di-Cbz-N''-triflylguanidine (4) is presented. The triflyldiurethane-protected guanidine 3 was utilized to guanidinylate primary and secondary amines under mild conditions with high yield in both solution and on solid phase.
- Feichtinger, Konrad,Sings, Heather L.,Baker, Tracy J.,Matthews, Kenneth,Goodman, Murray
-
p. 8432 - 8439
(2007/10/03)
-
- Conversion of alcohols to protected guanidines using the Mitsunobu protocol
-
An efficient method for the direct conversion of alcohols to guanidines is presented. A variety of alcohols react with 1 and 2 under Mitsunobu conditions to give the corresponding guanidines in high yield.
- Dodd, Dharmpal S.,Kozikowski, Alan P.
-
p. 977 - 980
(2007/10/02)
-
