64154-78-5Relevant articles and documents
COMPOSITIONS AND METHODS RELATED TO MOLECULAR CONJUGATION
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, (2021/06/11)
The invention relates to activated Michael acceptor (AMA) compounds that can undergo conjugation with biomolecules containing Michael donor moieties, thereby providing plasma-stable antibody-drug conjugates (ADCs). Pharmaceutical compositions of the ADCs are disclosed as well. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
VISUAL DETECTION OF PBD INDUCED DNA CROSSLINKS
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Page/Page column 41; 42, (2021/04/23)
The present invention relates to the field of oncology, laboratory tools and methods, and especially anti-tumor DNA crosslinking agents. Most patients with advanced solid tumors develop resistance to chemotherapy due to the ability of cancer cells to repair or tolerate sustained DNA damages. The inventors showed that the compounds according to the present invention allow the detection and visualization of alkylated DNA damages induced by PBDs without altering their DNA crosslinking ability. This enables the study of the effect and properties of PBDs. In particular, the present invention relates new derivates of PBD molecules and their synthesis. The present invention also relates to a method for visualizing DNA crosslinking; to a method for assessing the resistance of a tumor to a crosslinking agent and to a method for identifying a molecule or treatment for improving the efficiency of a crosslinking agent.
FUSED HETEROCYCLIC BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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, (2020/05/29)
The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
Synthesis and biological evaluation of a novel C8-pyrrolobenzodiazepine (PBD) adenosine conjugate. A study on the role of the PBD ring in the biological activity of PBD-conjugates
Bhakta, Sanjib,Brucoli, Federico,Ferguson, Lindsay,Fox, Keith R.,Wells, Geoff
, (2020/03/19)
Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD-ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids.
CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES
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Page/Page column 146; 150-151, (2020/01/31)
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates
Chowdari, Naidu S.,Zhang, Yong,McDonald, Ivar,Johnson, Walter,Langley, David R.,Sivaprakasam, Prasanna,Mate, Robert,Huynh, Tram,Kotapati, Srikanth,Deshpande, Madhura,Pan, Chin,Menezes, Daniel,Wang, Yichong,Rao, Chetana,Sarma, Ganapathy,Warrack, Bethanne M.,Rangan, Vangipuram S.,Mei-Chen, Sung,Cardarelli, Pina,Deshpande, Shrikant,Passmore, David,Rampulla, Richard,Mathur, Arvind,Borzilleri, Robert,Rajpal, Arvind,Vite, Gregory,Gangwar, Sanjeev
, p. 13913 - 13950 (2020/12/02)
A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studie
NOVEL BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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, (2019/12/24)
The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs)
Reid, Emily E.,Archer, Katie E.,Shizuka, Manami,McShea, Molly A.,Maloney, Erin K.,Ab, Olga,Lanieri, Leanne,Wilhelm, Alan,Ponte, Jose F.,Yoder, Nicholas C.,Chari, Ravi V.J.,Miller, Michael L.
supporting information, p. 2455 - 2458 (2019/07/30)
Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo.
BENZODIAZEPINE DERIVATIVES
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Page/Page column 138; 139; 190; 191, (2019/07/17)
The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formulae (I), (II) and (III). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.
ISOQUINOLIDINOBENZODIAZEPINES
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, (2018/04/13)
This disclosure provides novel isoquinolidinobenzodiazepines. These compounds can also be incorporated into antibody-drug conjugates.
