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
Reaction of a bis‐tetrazinyl pyridine pincer ligand, btzp, with a vanadium(III) reagent gives not a simple adduct but dichlorido{3‐methyl‐6‐[6‐(6‐methyl‐1,2,4,5‐tetrazin‐3‐yl‐κN2)pyridin‐2‐yl‐κN]‐1,4‐dihydro‐1,2,4,5‐tetrazin‐1‐yl‐κN1}oxidovanadium(IV) acetonitrile 2.5‐solvate, [V(C11H10N9)Cl2O]·2.5CH3CN, a species which X‐ray diffraction reveals to have one H atom added to one of the two tetrazinyl rings. This H atom was first revealed by a short intermolecular N...Cl contact in the unit cell and subsequently established, from difference maps, to be associated with a hydrogen bond. One chloride ligand has also been replaced by an oxide ligand in this synthetic reaction. This formula for the complex, [V(Hbtzp)Cl2O], leaves open the question of both ligand oxidation state and spin state. A computational study of all isomeric locations of the H atom shows the similarity of their energies, which is subject to perturbation by intermolecular hydrogen bonding found in X‐ray work on the solid state. These density functional calculations reveal that the isomer with the H atom located as found in the solid state contains a neutral radical Hbtzp ligand and tetravalent d1 V center, but that these two unpaired electrons are more stable as an open‐shell singlet and hence antiferromagnetically coupled. 相似文献
ABSTRACT. The analysis of the carbonyl I.R. band and the U.V. phoelectron spectroscopic data along with the ab-initio calculations and X-ray diffraction of α-(methylsulfinyl)- and α-(phenylsulfinyl)-acetophenones indicated the predominance of the cis rotamers over the qauche ones. 相似文献
The gadolinium (Gd) member of a new type of heteropolytungstates that contain one lanthanide and two transition metal ions in a triangular arrangement is reported. The compound NaK6Gd0.33 [((VO)2Gd(H2O)4K2(H2O)2(Na)(H2O)2)(α-B-AsW9O33)2]·24H2O (1) was prepared from acidified aqueous solutions of Na2WO4·2H2O, As2O3 and VOSO4·5H2O to which Gd3+ ions were added. The single crystal X-ray structure analysis (monoclinic, space group P21/m) shows that the anion consists of two [α-B-AsIIIW9O33]9? trilacunary Keggin-type units linked by two VO2+, one Gd3+ as well as weakly by two K+ and one Na+ ions, resulting in a sandwich-type structure with idealized C2v symmetry. The problem of positioning crystal lattice and special polyoxometalate sites with different cations is discussed also in connection with supramolecular chemistry aspects and as an option for further research. A fit of the magnetic susceptibility yielded exchange coupling constants of JVV = ?2.55 cm?1 (anti-ferromagnetic) between the vanadium ions and JGdV = 0.6 cm?1 (ferromagnetic) between the Gd and each of the two vanadium ions. The complete magnetochemical analysis also revealed a partial occupancy of the Na+ sites in the counter-cation–water system by Gd3+ ions (0.33 Gd3+ ions in total). 相似文献
Changes of total content of phenolic substances, alteration in total titratable acidity and differences in tartaric acid content in grapes of four white (Müller-Thurgau — MT, Pinot Blanc — Rulandské bílé in Czech, RB, Sauvignon (Sg), and Muscat Ottonel — Mu?kát Ottonel in Czech, MO) and two blue (Dornfelder — Df and Blue Frankish — Frankovka in Czech, Fr) grapevine varieties throughout their growth, ripening and maturing (July–November). Potentiometric titration was applied for the determination of total titratable acids in grapes (expressed as tartaric acid equivalents in g L?1). A spectrophotometric method according Rebelein based on the formation of a colored complex of ammonium metavanadate and tartaric acid was used for determination of tartaric acid in green juice made by pressing unripe grapes. A spectrophotometric method based on reduction of phosphomolybdato-tungsten complex in alkaline solution using Folin-Ciocalteau reagent was applied for determination of total content of phenolic substances (TCP).
In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c. 相似文献
JPC – Journal of Planar Chromatography – Modern TLC - This paper was aimed at analytical and antioxidant activity studies on a series of European beech (Fagus sylvatica L.) leaves... 相似文献