The Experts below are selected from a list of 1041 Experts worldwide ranked by ideXlab platform
Felix Kratz - One of the best experts on this subject based on the ideXlab platform.
-
evaluation of combination therapy schedules of doxorubicin and an acid sensitive albumin binding prodrug of doxorubicin in the mia paca 2 pancreatic xenograft model
International Journal of Pharmaceutics, 2013Co-Authors: Felix Kratz, Iduna Fichtner, Samar S Azab, Reiner Zeisig, Andre WarneckeAbstract:Abstract In this work, we evaluated combinations of doxorubicin with INNO-206, a (6-maleimidocaproyl)Hydrazone Derivative of doxorubicin (DOXO-EMCH) that is currently undergoing two phase II clinical trials, in a primarily chemoresistant tumor indication, i.e. pancreatic cancer. Thus, we compared the antitumor efficacy and tolerability of the following weekly intravenous treatments in the MIA PaCa-2 xenograft model: 3 × 6 mg doxorubicin (MTD), 3 × 24 mg/kg DOXO-EMCH (doxorubicin equivalents, MTD), 3 × 3 mg/kg doxorubicin followed 6 h later by 3 × 12 mg/kg DOXO-EMCH, and 3 × 12 mg/kg DOXO-EMCH followed 6 h later by 3 × 3 mg/kg doxorubicin. Whereas therapy with doxorubicin only produced a moderate tumor inhibition, all other therapy arms induced complete and partial remissions up to the end of the experiment on day 43. Although the total amount of doxorubicin equivalents is 72 mg/kg when DOXO-EMCH is administered alone, but only 45 mg/kg doxorubicin equivalents are administered in the combination regimens, the antitumor efficacy in all treated groups was essentially identical, a surprising finding of this study. However, there were significant differences in the tolerability as assessed by the body weight changes: whereas therapy at the MTD of DOXO-EMCH (3 × 24 mg/kg) produced a body weight loss of −16% including one death, therapy with 3 × 12 mg/kg DOXO-EMCH followed 6 h later by 3 × 3 mg/kg doxorubicin produced −7% body weight loss, and 3 × 3 mg/kg doxorubicin followed 6 h later by 3 × 12 mg/kg DOXO-EMCH produced a body weight gain of +2% as a clear indication of minimal systemic toxicity. In addition, cell culture experiments revealed additive to synergistic effects when MIA PaCa-2 cells were exposed to doxorubicin followed 6 h later to exposure of the albumin-bound form of DOXO-EMCH spanning a ratio of 1:5 to 5:1 (analyzed for synergistic, additive or antagonistic effects using the software program CalcuSyn®). This animal study demonstrates that the time-dependent schedule of an albumin-binding prodrug and a free drug has a critical influence on the overall tolerability. A combination of doxorubicin and DOXO-EMCH is currently being investigated in a phase Ib study.
-
INNO-206, the (6-maleimidocaproyl Hydrazone Derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model
Investigational New Drugs, 2010Co-Authors: R. Graeser, N. Esser, H. Unger, Iduna Fichtner, C. Unger, Felix KratzAbstract:The (6-maleimidocaproyl)Hydrazone Derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may provide enhanced antitumor activity of doxorubicin while improving the overall toxicity profile. Preclinically, INNO-206 has shown superior activity over doxorubicin in a murine renal cell carcinoma model and in breast carcinoma xenograft models. In this work, we compared the antitumor activity of INNO-206 and doxorubicin at their respective maximum tolerated doses in three additional xenograft models (breast carcinoma 3366, ovarian carcinoma A2780, and small cell lung cancer H209) as well as in an orthotopic pancreas carcinoma model (AsPC-1). INNO-206 showed more potent antitumor efficacy than free doxorubicin in all tumor models and is thus a promising clinical candidate for treating a broad range of solid tumors.
-
characterisation of the conjugate of the 6 maleimidocaproyl Hydrazone Derivative of doxorubicin with lactosaminated human albumin by 13c nmr spectroscopy
European Journal of Pharmaceutical Sciences, 2009Co-Authors: Carla Boga, Felix Kratz, Luigi Fiume, Michele Baglioni, Carlo Bertucci, Claudio Farina, Marcella Manerba, Marina Naldi, Giuseppina Di StefanoAbstract:Abstract In order to improve the efficacy of doxorubicin (DOXO) in the treatment of hepatocellular carcinomas, the drug was conjugated with lactosaminated human albumin (L-HSA), a hepatotropic drug carrier. Conjugation was performed using the (6-maleimidocaproyl)Hydrazone Derivative of the drug (DOXO-EMCH). The maleimide group of DOXO-EMCH reacts with the aminoacidic residues of the carrier forming stable bonds, whereas the Hydrazone bond is rapidly hydrolysed in the acidic endosomal and lysosomal compartments of the cells allowing the intracellular release of DOXO. To identify the amino acids of L-HSA involved in the bond with DOXO-EMCH, in the present study we synthesized this compound with the 2,3 carbon atoms of the maleimide moiety enriched in the 13C isotope and used this labelled DOXO-EMCH to prepare two types of L-HSA conjugate. Type I was prepared in analogy to those studied in the anticancer experiments using tris(2-carboxyethyl)phosphine (TCEP) to reduce l -cysteine disulfides and make the sulfhydryl groups available for the reaction with DOXO-EMCH; type II was synthesized omitting TCEP. By 13C NMR spectroscopy we could demonstrate that in type I conjugate cysteine was the only amino acid residue that reacted with DOXO-EMCH, whereas in type II conjugate lysine was the only amino acid in the reaction with DOXO-EMCH. When hydrolysed in an acidic medium to cleave the Hydrazone bond, type I conjugate released only DOXO, whereas type II conjugate also released a Derivative of the drug.
-
a novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive Hydrazone bond synthesis characterization and preliminary biological properties of the conjugate
European Journal of Pharmaceutical Sciences, 2004Co-Authors: Giuseppina Di Stefano, Felix Kratz, Marcella Lanza, Luca Merina, Luigi FiumeAbstract:Abstract The expression of the asialoglycoprotein receptor on the cells of the large majority of the well differentiated hepatocellular carcinomas can be exploited to improve the chemotherapy of these tumours by coupling anticancer agents to macromolecules taken up by the receptor. In line with this approach, in previous experiments we coupled doxorubicin (DOXO) to lactosaminated human albumin (L-HSA) using the (6-maleimidocaproyl)Hydrazone Derivative of the drug as an acid sensitive linker. Encouraging results were obtained in laboratory animals using L-HSA–DOXO. This conjugate, however, has the disadvantage of a difficult synthesis, which requires protein thiolation with iminothiolane and can hinder its preparation on a large scale. Here we describe a very simple method of coupling. The HS-groups required for the reaction with the maleimide moiety of DOXO–EMCH are made available in L-HSA by a cleavage of the protein disulphides achieved with tris(2-carboxyethyl) phosphine (TCEP). Contrary to thiolic reducing agents, the use of TCEP eliminates the need of an inert atmosphere and allows a one-step coupling reaction, without purification of the reduced protein before the addition of DOXO–EMCH. As the previous L-HSA–DOXO conjugate, the new conjugate accomplishes a very efficient liver targeting of the drug. This novel method of synthesis should facilitate the preparation of L-HSA–DOXO in the amounts required for clinical studies.
-
probing the cysteine 34 position of endogenous serum albumin with thiol binding doxorubicin Derivatives improved efficacy of an acid sensitive doxorubicin Derivative with specific albumin binding properties compared to that of the parent compound
Journal of Medicinal Chemistry, 2002Co-Authors: Felix Kratz, Andre Warnecke, Karin Scheuermann, Cornelia Stockmar, Jurgen Schwab, Peter Lazar, Peter Druckes, Norbert Esser, Joachim Drevs, Didier RognanAbstract:We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253−1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b) release of the albumin-bound drug in the acidic environment at the tumor site due to the incorporation of an acid-sensitive bond between the drug and the carrier. To investigate this therapeutic strategy in greater depth, four (maleinimidoalkanoyl)Hydrazone Derivatives of doxorubicin were synthesized differing in the length of the aliphatic spacer (1, −(CH2)2−; 2, −(CH2)3−; 3, −(CH2)5−; 4, −(CH2)7−). The albumin-binding doxorubicin prodrugs, especially the (6-maleimidocaproyl)Hydrazone Derivative of doxorubicin (3), are rapidly and selectively bound to the cysteine-34 position of endogenous albumin. 3 was distinctly superior to the parent compound doxorubicin in three animal tumor models (R...
Manami Kaneko - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis and evaluation of the highly selective and potent g protein coupled receptor kinase 2 grk2 inhibitor for the potential treatment of heart failure
Journal of Medicinal Chemistry, 2017Co-Authors: Tomohiro Okawa, Yoshio Aramaki, Mitsuo Yamamoto, Toshitake Kobayashi, Shoji Fukumoto, Yukio Toyoda, Tsutomu Henta, Akito Hata, Shota Ikeda, Manami KanekoAbstract:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone Derivative 5 and 1,2,4-triazole Derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole Derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeut...
-
Design, Synthesis, and Evaluation of the Highly Selective and Potent G‑Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
2017Co-Authors: Tomohiro Okawa, Yoshio Aramaki, Mitsuo Yamamoto, Toshitake Kobayashi, Shoji Fukumoto, Yukio Toyoda, Tsutomu Henta, Akito Hata, Shota Ikeda, Manami KanekoAbstract:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone Derivative 5 and 1,2,4-triazole Derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole Derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment
Özışık Hacı - One of the best experts on this subject based on the ideXlab platform.
-
2-[(2E)-2-(3-chloro-2-fluorobenzylidene)hydrazinyl]pyridine: Synthesis, spectroscopic, structural properties, biological activity and theoretical analysis
'Elsevier BV', 2021Co-Authors: Özçelik Nefise, Tunç Tuncay, Çelik, Raziye Çatak, Erzengin Mahmut, Özışık HacıAbstract:The newly synthesized Hydrazone Derivative: 2 [(2E)-2-(3-chloro-2-fluorobenzylidene)hydrazinyl] pyridine was synthesized. The characterization of the title compound was carried out by elemental analysis, FT-IR, H-1 NMR, C-13 NMR and UV-VIS measurements. The crystal structure was determined by the single crystal X-ray diffraction (XRD) method. In addition, the title compound was also subjected to its possible antioxidant activity with free radical scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals using 3,5-di-tert-butyl-4-hydroxy-toluene (BHT) as standard antioxidant. The theoratical structural calculations were carried out by the density functional theory using the B3LYP method with 6-311++G(2d,2p) basis set. The theoretical and experimental results obtained were examined and compared
-
2-[(2E)-2-(3‑chloro‑2-fluorobenzylidene)hydrazinyl]pyridine: Synthesis, spectroscopic, structural properties, biological activity and theoretical analysis
'Elsevier BV', 2021Co-Authors: Özçelik Nefise, Tunç Tuncay, Erzengin Mahmut, Çatak Çelik Raziye, Özışık HacıAbstract:The newly synthesized Hydrazone Derivative: 2-[(2E)-2-(3‑chloro‑2-fluorobenzylidene)hydrazinyl] pyridine was synthesized. The characterization of the title compound was carried out by elemental analysis, FT-IR, 1H NMR, 13C NMR and UV–VIS measurements. The crystal structure was determined by the single crystal X-ray diffraction (XRD) method. In addition, the title compound was also subjected to its possible antioxidant activity with free radical scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals using 3,5-di‑tert‑butyl‑4‑hydroxy‑toluene (BHT) as standard antioxidant. The theoratical structural calculations were carried out by the density functional theory using the B3LYP method with 6–311++G(2d,2p) basis set. The theoretical and experimental results obtained were examined and compared
-
Synthesis, spectroscopic, crystal structure, biological activities and theoretical studies. of 2-[(2E)-2-(2-chloro-6-fluorobenzylidene) hydrazinyllpyridine
'Elsevier BV', 2017Co-Authors: Özçelik, Nefise Dilek, Tunç Tuncay, Çelik, Raziye Çatak, Erzengin Mahmut, Özışık HacıAbstract:WOS: 000395604700011We report in this paper the synthesis, spectroscopic, crystal structure, biological activities and theoretical results of the title compound. The crystal structure was defined by the X-ray diffraction (XRD) method. In addition, this newly synthesized Hydrazone Derivative was also subjected to its possible antioxidant activity with free radical scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals using butylated hydroxytoluene (BHT) as standard antioxidant. The structural calculations were performed by the density functional theory using the B3LYP method with 6-311++G(2d,2p) basis set. The calculated values were compared with experimental results. (C) 2017 Elsevier B.V. All rights reserved.Aksaray University, Science and Technology Application and Research Center, Turkey of the State of Planning Organization [20101K120480]; Ataturk UniversityThe authors acknowledge the Aksaray University, Science and Technology Application and Research Center, Turkey, for the use of the Bruker Smart Breeze CCD diffractometer (purchased under grant 20101K120480 of the State of Planning Organization); Dr. Bans And from Ataturk University for NMR measurements
Giuseppina Di Stefano - One of the best experts on this subject based on the ideXlab platform.
-
characterisation of the conjugate of the 6 maleimidocaproyl Hydrazone Derivative of doxorubicin with lactosaminated human albumin by 13c nmr spectroscopy
European Journal of Pharmaceutical Sciences, 2009Co-Authors: Carla Boga, Felix Kratz, Luigi Fiume, Michele Baglioni, Carlo Bertucci, Claudio Farina, Marcella Manerba, Marina Naldi, Giuseppina Di StefanoAbstract:Abstract In order to improve the efficacy of doxorubicin (DOXO) in the treatment of hepatocellular carcinomas, the drug was conjugated with lactosaminated human albumin (L-HSA), a hepatotropic drug carrier. Conjugation was performed using the (6-maleimidocaproyl)Hydrazone Derivative of the drug (DOXO-EMCH). The maleimide group of DOXO-EMCH reacts with the aminoacidic residues of the carrier forming stable bonds, whereas the Hydrazone bond is rapidly hydrolysed in the acidic endosomal and lysosomal compartments of the cells allowing the intracellular release of DOXO. To identify the amino acids of L-HSA involved in the bond with DOXO-EMCH, in the present study we synthesized this compound with the 2,3 carbon atoms of the maleimide moiety enriched in the 13C isotope and used this labelled DOXO-EMCH to prepare two types of L-HSA conjugate. Type I was prepared in analogy to those studied in the anticancer experiments using tris(2-carboxyethyl)phosphine (TCEP) to reduce l -cysteine disulfides and make the sulfhydryl groups available for the reaction with DOXO-EMCH; type II was synthesized omitting TCEP. By 13C NMR spectroscopy we could demonstrate that in type I conjugate cysteine was the only amino acid residue that reacted with DOXO-EMCH, whereas in type II conjugate lysine was the only amino acid in the reaction with DOXO-EMCH. When hydrolysed in an acidic medium to cleave the Hydrazone bond, type I conjugate released only DOXO, whereas type II conjugate also released a Derivative of the drug.
-
a novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive Hydrazone bond synthesis characterization and preliminary biological properties of the conjugate
European Journal of Pharmaceutical Sciences, 2004Co-Authors: Giuseppina Di Stefano, Felix Kratz, Marcella Lanza, Luca Merina, Luigi FiumeAbstract:Abstract The expression of the asialoglycoprotein receptor on the cells of the large majority of the well differentiated hepatocellular carcinomas can be exploited to improve the chemotherapy of these tumours by coupling anticancer agents to macromolecules taken up by the receptor. In line with this approach, in previous experiments we coupled doxorubicin (DOXO) to lactosaminated human albumin (L-HSA) using the (6-maleimidocaproyl)Hydrazone Derivative of the drug as an acid sensitive linker. Encouraging results were obtained in laboratory animals using L-HSA–DOXO. This conjugate, however, has the disadvantage of a difficult synthesis, which requires protein thiolation with iminothiolane and can hinder its preparation on a large scale. Here we describe a very simple method of coupling. The HS-groups required for the reaction with the maleimide moiety of DOXO–EMCH are made available in L-HSA by a cleavage of the protein disulphides achieved with tris(2-carboxyethyl) phosphine (TCEP). Contrary to thiolic reducing agents, the use of TCEP eliminates the need of an inert atmosphere and allows a one-step coupling reaction, without purification of the reduced protein before the addition of DOXO–EMCH. As the previous L-HSA–DOXO conjugate, the new conjugate accomplishes a very efficient liver targeting of the drug. This novel method of synthesis should facilitate the preparation of L-HSA–DOXO in the amounts required for clinical studies.
Luigi Fiume - One of the best experts on this subject based on the ideXlab platform.
-
characterisation of the conjugate of the 6 maleimidocaproyl Hydrazone Derivative of doxorubicin with lactosaminated human albumin by 13c nmr spectroscopy
European Journal of Pharmaceutical Sciences, 2009Co-Authors: Carla Boga, Felix Kratz, Luigi Fiume, Michele Baglioni, Carlo Bertucci, Claudio Farina, Marcella Manerba, Marina Naldi, Giuseppina Di StefanoAbstract:Abstract In order to improve the efficacy of doxorubicin (DOXO) in the treatment of hepatocellular carcinomas, the drug was conjugated with lactosaminated human albumin (L-HSA), a hepatotropic drug carrier. Conjugation was performed using the (6-maleimidocaproyl)Hydrazone Derivative of the drug (DOXO-EMCH). The maleimide group of DOXO-EMCH reacts with the aminoacidic residues of the carrier forming stable bonds, whereas the Hydrazone bond is rapidly hydrolysed in the acidic endosomal and lysosomal compartments of the cells allowing the intracellular release of DOXO. To identify the amino acids of L-HSA involved in the bond with DOXO-EMCH, in the present study we synthesized this compound with the 2,3 carbon atoms of the maleimide moiety enriched in the 13C isotope and used this labelled DOXO-EMCH to prepare two types of L-HSA conjugate. Type I was prepared in analogy to those studied in the anticancer experiments using tris(2-carboxyethyl)phosphine (TCEP) to reduce l -cysteine disulfides and make the sulfhydryl groups available for the reaction with DOXO-EMCH; type II was synthesized omitting TCEP. By 13C NMR spectroscopy we could demonstrate that in type I conjugate cysteine was the only amino acid residue that reacted with DOXO-EMCH, whereas in type II conjugate lysine was the only amino acid in the reaction with DOXO-EMCH. When hydrolysed in an acidic medium to cleave the Hydrazone bond, type I conjugate released only DOXO, whereas type II conjugate also released a Derivative of the drug.
-
a novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive Hydrazone bond synthesis characterization and preliminary biological properties of the conjugate
European Journal of Pharmaceutical Sciences, 2004Co-Authors: Giuseppina Di Stefano, Felix Kratz, Marcella Lanza, Luca Merina, Luigi FiumeAbstract:Abstract The expression of the asialoglycoprotein receptor on the cells of the large majority of the well differentiated hepatocellular carcinomas can be exploited to improve the chemotherapy of these tumours by coupling anticancer agents to macromolecules taken up by the receptor. In line with this approach, in previous experiments we coupled doxorubicin (DOXO) to lactosaminated human albumin (L-HSA) using the (6-maleimidocaproyl)Hydrazone Derivative of the drug as an acid sensitive linker. Encouraging results were obtained in laboratory animals using L-HSA–DOXO. This conjugate, however, has the disadvantage of a difficult synthesis, which requires protein thiolation with iminothiolane and can hinder its preparation on a large scale. Here we describe a very simple method of coupling. The HS-groups required for the reaction with the maleimide moiety of DOXO–EMCH are made available in L-HSA by a cleavage of the protein disulphides achieved with tris(2-carboxyethyl) phosphine (TCEP). Contrary to thiolic reducing agents, the use of TCEP eliminates the need of an inert atmosphere and allows a one-step coupling reaction, without purification of the reduced protein before the addition of DOXO–EMCH. As the previous L-HSA–DOXO conjugate, the new conjugate accomplishes a very efficient liver targeting of the drug. This novel method of synthesis should facilitate the preparation of L-HSA–DOXO in the amounts required for clinical studies.
