- Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers
-
Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvβ3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3-) and its subclone CCRF-CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVβ3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
- Dal Corso, Alberto,Caruso, Michele,Belvisi, Laura,Arosio, Daniela,Piarulli, Umberto,Albanese, Clara,Gasparri, Fabio,Marsiglio, Aurelio,Sola, Francesco,Troiani, Sonia,Valsasina, Barbara,Pignataro, Luca,Donati, Daniele,Gennari, Cesare
-
-
Read Online
- First total synthesis of cyclic pentadepsipeptides Hikiamides A–C
-
The first total syntheses of naturally occurring cyclodepsipeptides Hikiamides A–C are described. The key linear pentapeptide precursors, prepared efficiently via Fmoc-solid-phase synthesis, were cyclized in dilute solution to provide the target Hikiamide
- Fu, Donglin,Rao, Xuemin,Xu, Jinyi,Tanabe, Genzoh,Muraoka, Osamu,Wu, Xiaoming,Xie, Weijia
-
-
Read Online
- Efficient and facile formation of two-component nanoparticles via aromatic moiety directed self-assembly
-
Here we present a two-component self-assembling system employing the interaction of aromatic groups (Fmoc) to construct nanoparticles. Spherical particles of around 70 nm were formed spontaneously by a simple trigonal Fmoc-conjugate, which were then stabi
- Wang, Weiping,Chau, Ying
-
-
Read Online
- Enzyme-responsive multifunctional magnetic nanoparticles for tumor intracellular drug delivery and imaging
-
Enzyme-responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)-conjugated, enzyme-cleavable peptide precursors were covalently tethered onto the surface of uniform silica-coated magnetic nanoparticles through click chemistry. This enzyme-responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression. Copyright
- Yang, Yanmei,Aw, Junxin,Chen, Kai,Liu, Fang,Padmanabhan, Parasuraman,Hou, Yanglong,Cheng, Zhen,Xing, Bengang
-
-
Read Online
- Thioether macrocycles of the microbisporicins via reductive desulfurization
-
The microbisporicins are the most potent lantibiotics isolated to-date. Cyclic tetra-, hexa- and octapeptides, inspired by this family of antimicrobial agents, have been synthesized from linear peptides. Generalized reaction conditions are reported for th
- Kutty, Samuel K.,Lutz, Joshua A.,Felder, Simon,Hahn, Philip,Taylor, Carol M.
-
-
Read Online
- Site-Specific Incorporation of Multiple Thioamide Substitutions into a Peptide Backbone via Solid Phase Peptide Synthesis
-
Among various peptide modification strategies, thioamide substitution by replacing the carbonyl oxygen atom of an amide bond with a sulfur atom constitutes an invaluable tool for chemical biology, for use in peptide drug discovery and protein structure-fu
- Yang, Jinhua,Wang, Changliu,Yao, Chaochao,Chen, Chunqiu,Hu, Yafang,He, Guifeng,Zhao, Junfeng
-
p. 1484 - 1494
(2020/01/02)
-
- Ynamide-Mediated Thiopeptide Synthesis
-
Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH2, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.
- Yang, Jinhua,Wang, Changliu,Xu, Silin,Zhao, Junfeng
-
supporting information
p. 1382 - 1386
(2019/01/08)
-
- POLYCONJUGATES FOR DELIVERY OF RNAI TRIGGERS TO TUMOR CELLS IN VIVO
-
The present invention is directed compositions for delivery of RNA interference (RNAi) triggers to integrin positive tumor cells in vivo. The compositions comprise RGD ligand- targeted amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or conjugate) are further covalently linked to an RNAi trigger.
- -
-
Page/Page column 36
(2015/02/25)
-
- A new synthesis of cystamine modified Eu3+ DOTAM-Gly-Phe-OH: A conjugation ready temperature sensitive MRI contrast agent
-
Several approaches towards asymmetrically derivatized peptide-decorated cyclens that yield lanthanide metal chelators, in which three of the nitrogen atoms of cyclen share a common substituent and the fourth nitrogen atom is differentially substituted, ha
- Suchy, Mojmir,Li, Alex X.,Bartha, Robert,Hudson, Robert H. E.
-
experimental part
p. 3588 - 3596
(2009/02/05)
-
- Synthesis of potent water-soluble tissue transglutaminase inhibitors
-
Dipeptide-based sulfonium peptidylmethylketones derived from 6-diazo-5-oxo-l-norleucine (DON) have been investigated as potential water-soluble inhibitors of extracellular transglutaminase. The lead compounds were prepared in four steps and exhibited pote
- Griffin, Martin,Mongeot, Alexandre,Collighan, Russell,Saint, Robert E.,Jones, Richard A.,Coutts, Ian G.C.,Rathbone, Daniel L.
-
scheme or table
p. 5559 - 5562
(2009/05/30)
-
- Design and synthesis of novel prodrugs of 2′-deoxy-2′-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues
-
DNA microarray analysis comparing human tumor tissues with normal tissues including hematopoietic progenitor cells resulted in identification of membrane dipeptidase as a prodrug activation enzyme. Novel prodrugs of 2′-deoxy-2′-methylidenecytidine (DMDC)
- Kohchi, Yasunori,Hattori, Kazuo,Oikawa, Nobuhiro,Mizuguchi, Eisaku,Isshiki, Yoshiaki,Aso, Kohsuke,Yoshinari, Kiyoshi,Shirai, Haruyoshi,Miwa, Masanori,Inagaki, Yukiko,Ura, Masako,Ogawa, Kotaroh,Okabe, Hisafumi,Ishitsuka, Hideo,Shimma, Nobuo
-
p. 2241 - 2245
(2008/02/03)
-
- Cobalamin conjugates for anti-tumor therapy
-
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently
- -
-
Page/Page column 17
(2008/06/13)
-
- Factors Affecting Conformation in Proline-Containing Peptides
-
(Equation presented) NMR was used to study the thermodynamics of the cis → trans isomerization for prolyl amide bonds in the compounds shown. The magnitude of Kt/c for C-terminal esters is greater than for the corresponding amides, signifying s
- Taylor, Carol M.,Hardre, Renaud,Edwards, Patrick J. B.,Park, Jae H.
-
p. 4413 - 4416
(2007/10/03)
-
- In the search for new anticancer drugs. 28. Synthesis and evaluation of highly active aminoxyl labeled amino acid derivatives containing the [N'-(2- chloroethyl)-N'-nitrosoamino]carbonyl group
-
The aminoxyl (nitroxyl) labeled (2-chloroethyl)nitrosocarbamoyl (CNC) derivatives of amino acids, i.e., N-[[N'-(2-chloroethyl)-N'- nitrosoamino]carbonyl]-A-(1-oxy-2,2,6,6-tetramethylpiperidin-4-yl)amides, A = glycyl (10a), A = L-alanyl (10b), A = L-valyl (10c), A = L-phenylalanyl (10d), were synthesized and evaluated in vitro for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 10a-d possessed activities ranging from 242 to 456% increase in life span (%ILS). All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 30 days. Compounds 10a-d were then tested in vivo against the murine lymphoid leukemia L1210. Compounds 10a-d exhibited, on day 60, a %ILS of 496, 663, 663, and 581, respectively. All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 60 days. The lipophilicities of compounds 10a-d were determined using the UV method. The %ILS parameters obtained against the P388 and L1210 tumor lines were correlated with the corresponding lipophilicities, and a trend was generally observed toward an increase in cytotoxicity with a concomitant decrease in hydrophobicity.
- Sosnovsky,Baysal,Erciyas
-
p. 999 - 1005
(2007/10/02)
-
