148579-57-1Relevant articles and documents
GLYCOSIDE-CONTAINING PEPTIDE LINKERS FOR ANTIBODY-DRUG CONJUGATES
-
, (2020/08/13)
The present disclosure provides antibody-drug conjugate structures, which include a cleavable linker that links the antibody to the drug and has a first cleavable moiety and a second cleavable moiety that hinders cleavage of the first cleavable moiety. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same.
PYRROLOBENZODIAZEPINE DIMER PRECURSOR AND LIGAND-LINKER CONJUGATE COMPOUND THEREOF
-
Paragraph 0133; 0135, (2020/02/18)
The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
Extended scaffold glucuronides: En route to the universal synthesis of O -aryl glucuronide prodrugs
Walther, Raoul,Jarlstad Olesen, Morten T.,Zelikin, Alexander N.
, p. 6970 - 6974 (2019/08/01)
We demonstrate that an extended scaffold based on a self-immolative linker (SIL) enables the universal production of O-aryl glucuronide prodrugs: high yield glucuronidation is performed on a precursor substrate (SIL) and the subsequent drug conjugation proceeds via less challenging chemical reactions.
Combatting implant-associated biofilms through localized drug synthesis
Walther, Raoul,Nielsen, Signe Maria,Christiansen, Rikke,Meyer, Rikke L.,Zelikin, Alexander N.
, p. 94 - 102 (2018/09/04)
Bacterial contamination of implantable biomaterials is a significant socioeconomic and healthcare burden. Indeed, bacterial colonization of implants after surgery has a high rate of incidence whereas concurrent prophylaxis using systemic antibiotics has limited clinical success. In this work, we develop enzyme-prodrug therapy (EPT) to prevent and to treat bacteria at interfaces. Towards the overall goal, novel prodrugs for fluoroquinolone antibiotics were developed on a privileged glucuronide scaffold. Whereas carbamoyl prodrugs were not stable and not suitable for EPT, glucuronides containing self-immolative linker between glucuronic acid masking group and the antibiotic were stable in solution and readily underwent bioconversion in the presence of β-glucuronidase. Surface coatings for model biomaterials were engineered using sequential polymer deposition technique. Resulting coatings afforded fast prodrug conversion and mediated antibacterial measures against planktonic species as evidenced by pronounced zone of bacterial growth inhibition around the biomaterial surface. These biomaterials coupled with the glucuronide prodrugs also effectively combatted bacteria within established biofilms and also successfully prevented bacterial colonization of the surface. To our knowledge, this is the first report of EPT engineered to the surface of biomaterials to mediate antibacterial measures.
CALICHEAMICIN DERIVATIVES AND ANTIBODY DRUG CONJUGATES THEREOF
-
, (2018/08/20)
The present invention is directed to novel calicheamicin derivatives useful as payloads in antibody-drug-conjugates (ADC's), and to payload-linker compounds and ADC compounds comprising the same; to pharmaceutical compositions comprising the same and to methods for using the same to treat pathological conditions such as cancer.
Self-powered microscale pumps based on analyte-initiated depolymerization reactions
Zhang, Hua,Yeung, Kimy,Robbins, Jessica S.,Pavlick, Ryan A.,Wu, Meng,Liu, Ran,Sen, Ayusman,Phillips, Scott T.
supporting information; experimental part, p. 2400 - 2404 (2012/04/23)
Pump it up: Insoluble polymer films that depolymerize to release soluble monomeric products when exposed to a specific analyte act as a microscale pump. Products formed as a result of depolymerization amplify the signal and create a concentration gradient
A structurally simple self-immolative reagent that provides three distinct, simultaneous responses per detection event
Nunez, Sean A.,Yeung, Kimy,Fox, Nicole S.,Phillips, Scott T.
, p. 10099 - 10113 (2012/02/05)
A general design is presented for a stimulus-responsive small molecule that is capable of responding to a specific applied chemical or physical signal by releasing two different types of pendant small molecules and a colorimetric indicator simultaneously. A key aspect of this design is the ease with which these reagents are prepared: typically, only four synthetic steps are required. Moreover, the modular construction strategy provides access to stimuli-responsive reagents that are capable of (i) responding to a variety of applied signals and (ii) releasing a number of different small molecules that contain primary alcohols, secondary alcohols, or phenols. These stimuli-responsive reagents are stable under physiological conditions (neither hydrolysis nor thermal degradation of the reagent occurs in significant quantity), and when they are exposed to the appropriate applied signal, they release both pendant small molecules and the colorimetric indicator completely within hours. Finally, unlike other functional groups, such as carbonates, that are used to connect alcohol-bearing molecules to controlled-release reagents, the linkage described in this article increases in hydrolytic stability (rather than decreases) as the pKa of the pendant alcohol decreases (Figure presented).
Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT)
Leu, Yu-Ling,Roffler, Steve R.,Chern, Ji-Wang
, p. 3623 - 3628 (2007/10/03)
Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was-connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20-80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of β-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal β- glucuronidase as well as for antibody-directed enzyme prodrug-therapy (ADEPT) of cancer.
Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy
Florent, Jean-Claude,Dong, Xia,Gaudel, Gilbert,Mitaku, Sofia,Monneret, Claude,Gesson, Jean-Pierre,Jacquesy, Jean-Claude,Mondon, Martine,Renoux, Brigitte,Andrianomenjanahary, Solo,Michel, Sylvie,Koch, Michel,Tillequin, Fran?ois,Gerken, Manfred,Czech, Joerg,Straub, Rainer,Bosslet, Klaus
, p. 3572 - 3581 (2007/10/03)
A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with β-gl
A methyl glucuronate prodrug of phosphorodiamidic mustard
Ghosh, Ajit K.,Farquhar, David
, p. 8795 - 8798 (2007/10/03)
4-[Methyl (β-D-glucopyranosyl)uronate]benzyl N,N,N',N'-tetrakis(2-chloroethyl) phosphorodiamidate, 3, was synthesized as a neutral prodrug of N,N,N',N'-tetrakis(2-chloroethyl) phosphorodiamidate mustard, 2c. In the presence of carboxylate esterase and β-D-glucuronidase, 3 was converted to 2c and 4-hydroxybenzyl alcohol, 7.
