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1.
Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers
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Alberto Dal Corso Dr. Michele Caruso Dr. Laura Belvisi Dr. Daniela Arosio Prof. Dr. Umberto Piarulli Dr. Clara Albanese Dr. Fabio Gasparri Dr. Aurelio Marsiglio Dr. Francesco Sola Dr. Sonia Troiani Dr. Barbara Valsasina Dr. Luca Pignataro Dr. Daniele Donati Prof. Dr. Cesare Gennari 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(18):6921-6929
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. 相似文献
2.
Giovanna Gasparri Fava Marisa Belicchi Ferrari Giovanni Casiraghi Gloria Rassu Pietro Spanu 《Journal of chemical crystallography》1991,21(5):629-633
The crystal structure of the title lactone, C20H30O9, a potential precursor of uncommon 11-carbon sugar derivatives, has been determined by single-crystal diffraction methods. The compound crystallizes in the orthorhombic space groupP212121 witha=15.581(3),b=14.047(2),c=9.888(2) Å, andZ=4. The structure was solved by direct methods and refined by full-matrix least-squares toR=0.054. The absolute configuration of the seven stereogenic carbon atoms was deduced as 4R, 5R, 6R, 7R, 8S, 9R, 10R, being (R)-(+)-glyceraldehyde its progenitor. An intramolecular O-HO hydrogen bond is present. Weak interaction C-HO links the molecules in sheets parallel to the (100) plane. 相似文献
3.
Giovanna Gasparri Fava Marisa Ferrari Belicchi Daniele Belletti Giovanni Casiraghi Gloria Rassu 《Journal of chemical crystallography》1991,21(3):261-264
The crystal structure of the title lactone, C13H18O7, has been determined by single crystal diffraction methods. The compound crystallizes in the monoclinic space groupP21 witha=13.231(2),b=10.248(2),c=5.348(1) Å,=96.66(2)°, andZ=2. A total of 1055 reflection intensities were recorded on a Siemens AED single-crystal diffractometer (CuK radiation) at room temperature. The structure was solved by direct methods and electron density calculations. Full-matrix least-squares refinement gaveR=0.055 for 946 unique reflections above 2(I). The absolute configuration of the six chiral carbon atoms was deduced as 4S, 5R, 6R, 7S, 9R, 10R (crystallographic numbering corresponds to C-6, 5, 4, 3, 2, 1 in the title compound). An intermolecular O-HO hydrogen bond joins the molecules in chains which run along the twofold screw axis. 相似文献
4.
5.
Giovanna Gasparri Fava Marisa Belicchi Ferrari Giorgio Pelosi Franca Zanardi Giovanni Casiraghi Gloria Rassu 《Journal of chemical crystallography》1996,26(7):509-513
The structure of 2,3-dideoxy-4-thio-d-arabino-heptonic acid 1,4-lactone has been determined by X-ray diffraction. Crystals of the compound are orthorhombic, space groupP212121, with cell dimensionsa=11.555(5),b=10.451(5),c=9.604(5) Å, andZ=4. The diffraction experiment has allowed to assign the absolute configuration (4R, 5R, 6R) to the chiral centers of the molecule. 相似文献
6.
7.
The thallium-barium double nitrite, TlBa2(NO2)5, is pyroelectric in the 77-600 K range and crystallizes in thePca2
1 space group. The lattice constants at 293 K are: a = 17.868(12),b = 4.934(3),c = 13-426(11) A (MoKa, λ = 0.71069 A). There are four stoichiometric units in the unit cell of volume V= 1184(1) A3 (D
o = 3.98,D
x = 3.979 Mgm−3),F (000) = 1232, μ = 20.36mm−1. The crystal structure was solved by Patterson and Fourier methods and refined by least-squares to a final conventional agreement
indexR = 0.053 for 1371 independent reflections collected in a θ range of 3–30°, using MoKα radiation. There are two independent
barium atoms surrounded by NO
2
−
groups, both with coordination number 10 and distances in the ranges Ba-O = 2.69(4)-3.18(4) A and Ba-N = 3.01(4)-3.18(4)
A. The environment of thallium is clearly affected by the lone-pair stereoactivity and involves 12 Tl-O and Tl-N contacts
less than 3.5A, but only four Tl-O distances are shorter than 3 A (min. 2.76(2), max. 2.85(3) A), with a pyramidal coordination
and thallium at the apex of the pyramid. All these coordination polyhedra are joined in chains running along the shortest
lattice vector [010].
The single crystal electronic spectra, studied in absorption with polarized light and in photostimulated emission, are interpreted
as due to transitions involving NO
2
−
electronic levels perturbed by Tl+, whose spin-orbit interaction makes probable also the forbidden singlet-triplet transitions, in agreement with the interpretative
picture given for post-transition metal nitrites. 相似文献
8.
High-content analysis of kinase activity in cells 总被引:1,自引:0,他引:1
Gasparri F Sola F Bandiera T Moll J Galvani A 《Combinatorial chemistry & high throughput screening》2008,11(7):523-536
High-content analysis (HCA) is a term used to describe techniques involving multiplexed analysis of fluorescent markers to measure multiple cellular responses to biological stimuli or drug treatment. HCA is usually based on automated microscopy or related technologies, and its value lies in providing multiparametric information on single cells within a population. During the last decade, several HCA approaches have been developed and applied to assess cellular mechanism of action of pharmacologically relevant compounds identified through biochemical screening or similar in vitro methods. With automation and instrument development, these approaches have evolved to the extent that the technique is now routinely used in screening applications, including primary HTS on compound collections. Here, we review the field and discuss in particular the application of HCA to the discovery of small molecule inhibitors targeting kinases which are implicated in Oncology. 相似文献
9.
Marisa Belicchi Ferrari Giovanna Gasparri Fava Giorgio Pelosi Gianfranco Denti 《Journal of chemical crystallography》1997,27(4):257-261
[3,6-bis(2-pyridyl)pyridazine-N 1,N2]bis(triphenylphosphine) copper(I) hexafluorophosphate crystallizes in space group $P\bar 1$ with cell dimensionaa=14.050(2),b=11.941(2),c=15.200(2) Å, α=71.28(1), β=67.02(1), and γ=84.78(2)o. In the title compound, the mononuclear cation consists of a tetrahedral copper(I) center involving two nitrogen donors of the 3,6-bis(2-pyridyl)pyridazine (dppn) and two P atoms of the triphenylphosphine molecules. In the dppn ligand the two non-coordinating N atoms (one from pyridine and one from pyridazine) are mutallytrans. 相似文献
10.
Some natural compounds, including flavonoids, are active in vasculature re-growth during hair follicle disruption, but their effects have not been yet evaluated directly on microvascular endothelial cells. Skin vascularisation regulates the physiological blood supply required for hair growth and its dysregulation is the basis of several human diseases. Follicle-derived vascular endothelial growth factor (VEGF) release from follicular keratinocytes promotes perifollicular vascularisation and increases follicle and hair size, while blockade of VEGF-mediated angiogenesis leads to impaired hair growth. Here, we tested three flavonoids, namely visnadin (VSD), hesperidin (HSP) and baicalin (BC), on cultured human microvascular endothelial cells (HMEC), comparing their effects with minoxidil (MXD), a synthetic drug broadly used in the treatment of androgenetic alopecia. The response to these compounds was assayed in terms of endothelial survival, proliferation, tubulogenesis and proangiogenic signalling. We show that BC promotes HMEC proliferation, while both VSD and MXD enhance tubulogenesis. Interestingly, only HSP increases VEGFR-2 phosphorylation. 相似文献