- Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics
-
Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.
- Low, Stewart A.,Yang, Jiyuan,Kopeek, Jindich
-
-
Read Online
- A general solid phase method for the preparation of diverse azapeptide probes directed against cysteine proteases
-
(Chemical Equation Presented) A solid phase approach is presented for the synthesis of azapeptide inhibitors and activity based probes (ABPs) for cysteine proteases. This synthetic method allows the incorporation of diverse reactive warheads linked to different peptide recognition elements. Application of this method to the synthesis of a series of caspase probes is described.
- Kato, Daisuke,Verhelst, Steven H. L.,Sexton, Kelly B.,Bogyo, Matthew
-
-
Read Online
- A hydroxamic-acid-containing nucleoside inhibits DNA repair nuclease SNM1A
-
Nine modified nucleosides, incorporating zinc-binding pharmacophores, have been synthesised and evaluated as inhibitors of the DNA repair nuclease SNM1A. The series included oxyamides, hydroxamic acids, hydroxamates, a hydrazide, a squarate ester and a squaramide. A hydroxamic acid-derived nucleoside inhibited the enzyme, offering a novel approach for potential therapeutic development through the use of rationally designed nucleoside derived inhibitors.
- Doherty, William,Dürr, Eva-Maria,Baddock, Hannah T.,Lee, Sook Y.,McHugh, Peter J.,Brown, Tom,Senge, Mathias O.,Scanlan, Eoin M.,McGouran, Joanna F.
-
supporting information
p. 8094 - 8105
(2019/09/19)
-
- Aza-amino acids disrupt β-sheet secondary structures
-
Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect of a single aza-amino acid incorporation located in the upper β-strand at a hydrogen-bonded (HB) site of a β-hairpin model peptide (H-Arg-Tyr-Val-Glu-Val-d-Pro-Gly-Orn-Lys-Ile-Leu-Gln-NH2) is reported. Specifically, analogs in which valine3 was substituted for aza-valine3 or aza-glycine3 were synthesized, and their β-hairpin stabilities were examined using Nuclear Magnetic Resonance (NMR) spectroscopy. The azapeptide analogs were found to destabilize β-hairpin formation compared to the parent peptide. The aza-valine3 residue was more disruptive of β-hairpin geometry than its aza-glycine3 counterpart.
- McMechen, Michael A.,Willis, Evan L.,Gourville, Preston C.,Proulx, Caroline
-
-
- Synthetic method of Fmoc-Aza-beta3Leu-OH
-
The invention discloses a synthetic method of Fmoc-Aza-beta3Leu-OH. The method comprises the following steps: enabling FMOC-Cl and hydrazine hydrate to have nucleophilic substitution to obtain FMOC-based formate as shown in formula A1; enabling 2-methyl propanal and the obtained Fmoc-based formate as shown in the formula A1 to have condensation reaction to obtain hydrazone as shown in formula A2;enabling the obtained hydrazone as shown in the formula A2 to have reduction reaction with reducing agent sodium cyanoborohydride to obtain Fmoc-Azabeta3Leu hydrazone as shown in formula A3; then enabling the Fmoc-Azabeta3Leu hydrazone as shown in the formula A3 to have nucleophilic substitution with tert-butyl bromoacetate to obtain FmocAza-beta3Leu-OtBu as shown in formula A4; and finally enabling the obtained FmocAza-beta3Leu-OtBu as shown in the formula A4 to have degreasing reaction with dichloromethane introduced with HCl gas to obtain a target product FmocAza-beta3Leu-OH as shown in formula A5. The preparation method provided by the invention is mild in reaction condition, a Fmoc protective group can be easily removed by utilizing a mild alkaline condition, the operation is simple,the route is simple and effective, and the applicability is wide.
- -
-
Paragraph 0032; 0033; 0034
(2018/07/07)
-
- 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 34
(2017/12/27)
-
- A New Method for the Synthesis of Oxadiazine Insecticide Indoxacarb
-
9-Fluorenylmethoxycarbonyl was a good protecting group in the field of chemical industry. In the present paper, a new approach for the synthesis of oxadiazine insecticides indoxacarb used 9-fluorenylmethoxycarbonyl as protected group, and triphosgene for chloroformylation. A convenient synthesis of 9-fluorenylmethoxycarbonylhydrazine can be achieved by the nucleophilic substitution reaction of 9-fluorenylmethyl chloroformate and hydrazine hydrate. 4a-Methyl-2-(9-fluorenylmethyl)-7-chloro-indeno [1,2e][1,3,4]oxadia zine-2,4a (3H,5H)-dicarboxylate can be produced via ketone -hydrazine crosslink reaction and cyclization. A preparation of carbamic acid-(chlorocarbonyl)-[(4-trifluoromethoxy) phenyl] me ester can be obtained by the chloroformylation of triphosgene. Finally, the deprotection of 9-fluorenylmethoxy carbonyl and condensation with carbamic acid-(chlorocarbonyl)-[(4-trifluoromethoxy) phenyl] me ester can afford indoxacarb in good yield. A new method for the synthesis of oxadiazine insecticides indoxacarb used 9-fluorenylmethoxycarbonyl-protected group to produce 9-?fluorenylmethoxycarb?onylhydrazine, then through the ketone–hydrazine crosslink reaction, cyclization, deprotection, chloroformylation, and condensation in good yield.
- Xu, Defeng,Guan, Jing,Xu, Xing,Gong, Shunze,Xu, Hui
-
p. 1469 - 1473
(2016/09/23)
-
- Azapeptides as CD36 binding compounds
-
An azapeptide compound of Formula I: A-(Xaa)a-N(RA)—N(RB)—C(O)-(Xaa′)b-B??I.
- -
-
Page/Page column 43
(2015/09/23)
-
- CYCLIC AZAPEPTIDES AS INTEGRIN MARKERS
-
The present application is directed to radiolabeled cyclic polyazapeptides, pharmaceutical compositions comprising radiolabeled cyclic polyazapeptides, and methods of using the radiolabeled cyclic polyazapeptides. Such polyazapeptides can be used in imaging studies, such as Positron Emitting Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).
- -
-
Paragraph 0093
(2015/09/28)
-
- Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a
-
The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the d-Trp2, Ala3, or Trp4 position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the d-Trp2 residue proved important for CD36 receptor affinity; however, His1 could be replaced by Ala1 without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr4]-GHRP-6 (15), [Ala1, azaPhe 2]-GHRP-6 (16), and [azaLeu3, Ala6]-GHRP-6 (33) all exhibited antiangiogenic activity.
- Proulx, Caroline,Picard, émilie,Boeglin, Damien,Pohankova, Petra,Chemtob, Sylvain,Ong, Huy,Lubell, William D.
-
scheme or table
p. 6502 - 6511
(2012/10/08)
-
- Cyclic aza-peptide integrin ligand synthesis and biological activity
-
Aza-peptides are obtained by replacement of the α-C-atom of one or more amino acids by a nitrogen atom in a peptide sequence. Introduction of aza-residues into peptide sequences may result in unique structural and pharmacological properties, such that aza-scanning may be used to probe structure-activity relationships. In this study, a general approach for the synthesis of cyclic aza-peptides was developed by modification of strategies for linear aza-peptide synthesis and applied in the preparation of cyclic aza-pentapeptides containing the RGD (Arg-Gly-Asp) sequence. Aza-amino acid scanning was performed on the cyclic RGD-peptide Cilengitide, cyclo[R-G-D-f-N(Me)V] 1, and its parent peptide cyclo(R-G-D-f-V) 2, potent antagonists of the αvβ3, αvβ5, and α5β1 integrin receptors, which play important roles in human tumor metastasis and tumor-induced angiogenesis. Although incorporation of the aza-residues resulted generally in a loss of binding affinity, cyclic aza-peptides containing aza-glycine retained nanomolar activity toward the αvβ3 receptor.
- Spiegel, Jochen,Mas-Moruno, Carlos,Kessler, Horst,Lubell, William D.
-
scheme or table
p. 5271 - 5278
(2012/09/25)
-
- Solvent-free synthesis of hydrazones and their subsequent N-alkylation in a Ball-mill
-
A large variety of Boc-, Bz-, Ts-, and Fmoc- protected hydrazones were prepared via condensation of an equimolar amount of carbonyl-compound and the corresponding hydrazine using a ball-mill. Hydrazones were always obtained in a quantitative yield and no solvents were used at any step. In a second step, we realized the first solvent-free N-allylation and N-benzylation of these hydrazones.
- Nun, Pierrick,Martin, Charlotte,Martinez, Jean,Lamaty, Frédéric
-
supporting information; experimental part
p. 8187 - 8194
(2011/10/31)
-
- 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)
-
- Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI)
-
Human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.1) is a novel putative drug target for the treatment of inflammatory diseases. Using 1 as a starting point (IC50 > 10 μM), we have improved potency by more than 500-fold and successfully identified novel inhibitors of DPPI via screening of a one-bead-two-compounds library of semicarbazide derivatives. Selected compounds were shown to inhibit intracellular DPPI in RBL-2H3 cells. These compounds were further characterized for adverse effects on HepG2 cells (cytotoxicity and viability) and their metabolic stability in rat liver microsomes was estimated. One of the most potent inhibitors, 8 (IC50 = 31 ± 3 nM; Ki = 45 ± 2 nM, competitive inhibition), is selective for DPPI over other cysteine and serine proteases, has a half-life of 24 min in rat liver microsomes, shows approximately 50% inhibition of intracellular DPPI at 20 μM and is noncytotoxic.
- Bondebjerg, Jon,Fuglsang, Henrik,Valeur, Kirsten Rosendal,Kaznelson, Dorte Wissing,Hansen, Johnny Arnsdorf,Pedersen, Rene Orup,Krogh, Berit Olsen,Jensen, Bo Skaaning,Lauritzen, Conni,Petersen, Gitte,Pedersen, John,Naerum, Lars
-
p. 4408 - 4424
(2007/10/03)
-
- PROTEASE INHIBITORS
-
A monoacyl semicarbazide of the general formula (I): (I), or a pharmaceutically acceptable salt or ester thereof, is capable of selectively inhibiting dipeptidyl-peptidase I (DPP-I), also known as cathepsin C. A compound of the invention is useful as an active substance for the treatment of inflammation, type 2 diabetes, asthma, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, Papillon Lefevre syndrome, Haim Munk syndrome, gum disease, periodontitis, rheumatoid arthritis, Huntington’s disease, Chaga’s disease, Alzheimer’s disease, sepsis or for application in target cell apoptosis.
- -
-
-
- NON-PEPTIDIC BRS-3 AGONISTS
-
The invention relates to novel compounds having a selective BRS-3 agonistic action and corresponding to general formula (I) wherein A1, A2, A3, R1, R2, R3, Ar1, Ar2, Ar3, m and n have the designations cited in the description. The invention also relates to pharmaceuticals containing said compounds and to methods for producing compounds of formula (I).
- -
-
-
- Process for making peptides
-
A process for the solid phase synthesis of peptides containing a C-terminal aza-amino acid, for example the decapeptide goserelin, which comprises:(i) reacting an active ester or imidazolide of an N-protected aza-amino acid either with an appropriate reactive solid support in the case of the synthesis of a peptide containing a C-terminal aza-amino acid, or with a peptide which is attached to a solid support in the case of the synthesis of a peptide containing a non-C-terminal aza-amino acid;(ii) carrying out further conventional solid phase peptide synthesis steps to add sequentially further amino acids, to form a peptide with the required amino acid sequence bound to the solid support;(iii) cleaving the peptide from the solid support, and optionally(iv) reacting the product so formed with hydrazine to remove any acyl groups which have been formed on serine, arginine, tyrosine, threonine or hydroxyproline during the synthesis.
- -
-
-
