- AHPPA derivative and its preparation method
-
The invention discloses AHPPA derivatives and a preparation method thereof. The preparation method utilizes a diethylzinc-stannic chloride mixture with a mole ratio of 1: 2-4 as a catalyst, improves a reaction temperature and a yield and is suitable for industrial production.
- -
-
Paragraph 0010; 0016; 0017; 0017; 0018
(2017/04/18)
-
- Helices with additional H-bonds: crystallographic conformations of α,γ-hybrid peptides helices composed of β-hydroxy γ-amino acids (statines)
-
β-Hydroxy-γ-amino acids (Statines) are a class of naturally occurring non-ribosomal amino acids frequently found in many peptide natural products. Peptidomimetics constituted with statines have been used as inhibitors for various aspartic acid proteases. In contrast to the synthetic γ-amino acids, very little is known about the folding behavior of these naturally occurring β-hydroxy γ-amino acids. To understand the folding behavior of statines, three α,γ-hybrid peptides P1 (Ac-Aib-γPhe-Aib-(R, S)Phesta-Aib-γPhe-Aib-CONH2), P2 (Ac-Aib-γPhe-Aib-(S, S)Phesta-Aib-γPhe-Aib-CONH2), and P3 (Ac-Aib-γPhe-Aib-(S, S)Phesta-Aib-(S, S)Phesta-Aib-CONH2) were synthesized on solid phase and their helical conformations in single crystals were studied. Results suggest that both syn and anti diastereoisomers of statines can be accommodated into the helix without deviating overall helical conformation of α,γ-hybrid peptides. In comparison with syn diastereoisomer, the anti diastereoisomer was found to be directly involved in the intramolecular H-bonding with the backbone carbonyl groups (i to i + 3) similar to the backbone amide NHs in the helix.
- Malik, Ankita,Kumar, Mothukuri Ganesh,Bandyopadhyay, Anupam,Gopi, Hosahudya N.
-
-
- Novel renin inhibitors containing derivatives of N-alkylleucyl-β-hydroxy-γ-amino acids
-
In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-β-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic β-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10-6-10-9 M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10-9 M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.
- Winiecka, Iwona,Jaworski, Pawe?,Mazurek, Aleksander Pawe?,Marsza?ek, Dorota,Goldnik, Anna,Sokulski, Daniel
-
p. 106 - 115
(2016/02/09)
-
- Exploring β-hydroxy γ-amino acids (statines) in the design of hybrid peptide foldamers
-
The synthesis and characterization of syn and anti β-hydroxy γ-amino acid (statine) diastereoisomers, their utilization in the design of hybrid peptide foldamers, and their single crystal conformations are studied.
- Bandyopadhyay, Anupam,Malik, Ankita,Kumar, Mothukuri Ganesh,Gopi, Hosahudya N.
-
p. 294 - 297
(2014/01/23)
-
- Stereoselective synthesis of four possible isomers of streptopyrrolidine
-
The synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R, 5S)-streptopyrrolidine (3) and (4S,5S)-strepto- pyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reacti
- Mohapatra, Debendra K.,Thirupathi, Barla,Das, Pragna P.,Yadav, Jhillu S.
-
experimental part
p. 34 - 39
(2011/03/22)
-
- Mechanism-based inhibitors of the aspartyl protease plasmepsin II as potential antimalarial agents
-
Four aspartyl proteases known as plasmepsins are involved in the degradation of hemoglobin by Plasmodium falciparum, which causes a large percentage of malaria deaths. The enzyme plasmepsin II (Plm-II) is the most extensively studied of these aspartyl proteases and catalyzes the initial step in the breakdown of hemoglobin by the parasite. Several groups have reported the design, synthesis, and evaluation of reversible peptidomimetic inhibitors of Plm II as potential antimalarial agents. We now report four peptidomimetic analogues, compounds 6-9, which are rationally designed to act as mechanism-based inhibitors of Plm II. Three of these analogues produce potent irreversible inactivation of the enzyme with IC50 values in the low nanomolar range. Of these three compounds, two retain the low micromolar IC 50 values of the parent compound in Plasmodium falciparum (clone 3D7) infected erythrocytes. These analogues are the first examples of fully characterized mechanism-based inactivators for an aspartyl protease and show promise as novel antimalarial agents.
- Gupta, Deepak,Yedidi, Ravikiran S.,Varghese, Sheeba,Kovari, Ladislau C.,Woster, Patrick M.
-
experimental part
p. 4234 - 4247
(2010/08/22)
-
- Solid-Phase Synthesis of β-Lactams via the Miller Hydroxamate Approach
-
(Matrix Presented) β-Lactams were prepared on solid phase starting from serine, threonine, or other β-hydroxyacids derived from naturally occurring amino acids and a resin bound hydroxylamine. The ring closure was carried out under Mitsunobu conditions. The amino group present on the β-lactam was used to assemble a short peptide. After a reductive cleavage with Sml2, β-lactam-containing peptides were obtained.
- Meloni, Marco Massimiliano,Taddei, Maurizio
-
p. 337 - 340
(2007/10/03)
-
- A Novel, Facile and Diastereoselective Synthesis of (3S,4S) and (3R,4S)-N-Me-AHPPA
-
Diastereoselective syntheses of (3S,4S) and (3R,4S)-N-methyl-AHPPA are achieved via a novel Wittig reaction of an oxazolidinone followed by reduction.
- Reddy, G. Vidyasagar,Rao, G. Venkat,Iyengar, D. S.
-
p. 703 - 704
(2007/10/03)
-
- Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-Deoxyhapalosin
-
Hapalosin (2), a 12-membered cyclic depsipeptide possessing MDR-reversing activity, and analogues (3) and (4) have been synthesized using macrolactamization as an important ring-forming step. Three building blocks: (2S, 3R)-3-(tert-butyldimethylsilyloxy)-2-methyl-decanoic acid (13), benzyl (S)-2-hydroxy-3-methylbutanate (14), and (4S,3R)-4-(benzyloxycarbonyl-methylamino)-3-methoxymethoxy-5-phenyl-pentanoic acid (28) were prepared from Evans's chiral imide (9), l-valine, and l-N-Boc phenylalanine (17), respectively, and were assembled together by applying twice Yamaguchi's coupling methodology. A new and efficient selective N-methylation of γ-hydroxy-β-amino ester taking advantage of the vicinal amino alcohol function was uncovered in the course of this study. Thus, treatment of compound 19 with HCHO in the presence of catalytic amount of pTsOH followed by reduction (NaBH3CN, TFA, CH2Cl2) of the so-formed oxazolidine 24 gave the N-methylated product 25. Furthermore, a dual role of oxazolidine as protecting group of vicinal amino alcohol and latent N-methyl function was established which allowed synthesizing both hapalosin (2) and N-desmethylhapalosin (3) from the same linear precursor 32 in a step-efficient and atom economic way. In contrast to hapalosin (2) and N-desmethyl analogue (3), the amide bond of 8-deoxy hapalosin (4) exists at room temperature (CDCl3) exclusively in s-cis conformation as evidenced by NOE studies. This observation has been explained on the basis of computational studies. No significant MDR reversing activity of 8-deoxy hapalosin (4) was observed in K562 R and S/Adriblastine against human erythroleucemic cell lines indicating thus the important contribution of hydroxy group to the bioactivity of hapalosin. Copyright (C) 1999 Elsevier Science Ltd.
- Wagner, Bjoern,Gonzalez, Gabriel Islas,Tran Hun Dau, Marie Elise,Zhu, Jieping
-
p. 737 - 747
(2007/10/03)
-
- New Approach to the Coupling if γ-Amino β-Hydroxy Acids and ν,γ-Dihydroxy Acids with α-Amino Acid Esters
-
α,α-Dichloro β-lactones, readily obtained by a highly diastereoselective cycloaddition of dichloroketene to N-Boc-α-amino aldehydes and α-(silyloxy) aldehydes, coupled efficiently with α-amino acid esters leading, after dehalogenation with H2 over 10percent Pd on charcoal, to peptide mimics under mild reaction conditions.
- Palomo, Claudio,Miranda, Jose I.,Linden, Anthony
-
p. 9196 - 9201
(2007/10/03)
-
- Synthesis of N-protected γ-amino-β-keto-esters from urethane N-carboxyanhydrides (UNCAs)
-
N-protected γ-amino-β-keto-esters were synthesized from the corresponding N-protected N-carboxyanhydride (UNCAs) by reaction with the lithium enolate of ethyl acetate in good yields. These compounds are precursors of statine derivatives.
- Paris, Marielle,Fehrentz, Jean-Alain,Heitz, Annie,Loffet, Albert,Martinez, Jean
-
p. 8489 - 8492
(2007/10/03)
-
- Synthesis of hapalosin and 8-deoxy-hapalosin
-
Hapalosin, a new MDR reversing agent, and its congener 8-deoxyhapalosin have been synthesized via macrolactamization. A new procedure for selective N-methylation of a vicinal amino alcohol is uncovered in the course of this study.
- Wagner, Bjoern,Beugelmans, Rene,Zhu, Jieping
-
p. 6557 - 6560
(2007/10/03)
-
- Synthesis and anti-human immunodeficiency virus type 1 activities of new peptido-nucleoside analogues
-
In order to investigate whether antiproteasic peptides coupled to anti-reverse transcriptase nucleosides can act as inhibitors at the different stages of the HIV life cycle, various peptido-nucleosides were synthesized using methodologies involving (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as a coupling reagent between the N4-cytosinyl moiety and the peptide carboxy terminus. The anti-HIV-1 activity in MT4 cells of this new class of compounds and their anti-HIV protease activities were determined. Fourteen peptido-nucleosides have been synthesized and six act against both the HIV-protease and viral replication in vitro. Although the activity of the most potent compounds against HIV was found to be one order of magnitude lower than that of the parent nucleoside drug 2',3'-dideoxy-3'-thiacytidine, this new class of compound could be of biological interest. Indeed, since the in vitro half-lives (t( 1/2 )) of the hydrolysis of the most potent compounds in human plasma were found to be longer than 2.5 h, these analogues could reach the infected cells in their structural integrity. This observation does not exclude that these compounds may exert their antiviral effects as combined prodrugs through extracellular or intracellular hydrolysis.
- Camplo,Niddam,Barthelemy,Faury,Mourier,Simon,Charvet,Trabaud,Graciet,Chermann,Kraus
-
p. 789 - 800
(2007/10/03)
-
- Diastereoselective Cycloaddition of Dichloroketene with α-Oxyaldehydes and α-Amino Aldehydes
-
A new route to natural products containing 1,2-diol and 1,2-amino alcohol subunits based on the cycloaddition of dichloroketene to α-oxyaldehydes and α-amino aldehydes is demonstrated.
- Palomo, Claudio,Miranda, Jose Ignacio,Cuevas, Carmen,Odriozola, Jose Manuel
-
p. 1735 - 1736
(2007/10/02)
-
- Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
-
Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials.Six approaches for the large-scale synthesis of this compound have been studied.All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5.They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation.The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1.Kilogram quantities of Ro 31-8959 have been prepared using this route.
- Parkes, Kevin E. B.,Bushnell, David J.,Crackett, Peter H.,Dunsdon, Stephen J.,Freeman, Andrew C.,et al.
-
p. 3656 - 3664
(2007/10/02)
-
- SYNTHESIS OF ASATINE AND ITS ANALOGUES BY HOMOGENEOUS ASYMMETRIC HYDROGENATION
-
Diastereoselective hydrogenation of N-protected γ-amino β-keto esters catalyzed by BINAP-Ru(II) complexes provides an efficient entry to the statine series with high enantiomeric purities.
- Nishi, T.,Kitamura, M.,Ohkuma, T.,Noyori, R.
-
p. 6327 - 6330
(2007/10/02)
-
- A Facile Synthesis of Statine and Analogues by Reduction of β-Keto Esters Derived from Boc-Protected Amino Acids. HPLC Analyses of Their Enantiomeric Purity
-
The synthesis of γ-amino-β-keto ester derivatives 3a-e from N-Boc-protected L-amino acids by N,N'-carbonyldiimidazole activation and treatment with the magnesium enolate of hydrogen ethyl malonate is described.Racemization during activation, which depende
- Maibaum, Juergen,Rich, Daniel H.
-
p. 869 - 873
(2007/10/02)
-