1204-69-9Relevant academic research and scientific papers
METHODS FOR INDUCING BIOORTHOGONAL REACTIVITY
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Page/Page column 31-32, (2017/07/06)
A method for catalytically converting a dihydrotetrazine 1 into a tetrazine 2, wherein one R group on the dihydrotetrazine 1 is a substituted or unsubstituted aryi, heteroaryl, alkyl, alkenyl, alkynyl, carbonyl, or heteroatom-containing group, and the other R group is selected from the group consisting of H and substituted or unsubstituted aryl, heteroaryl, alkyl, alkenyl, alkynyl, carbonyl,-or heteroatom-containing groups; 1, 2 wherein the method comprises oxidizing dihydrotetrazine 1 in a reaction medium in the presence of a catalyst and a stoichiometric oxidant.
Reactive oxygen species (ROS) inducible DNA cross-linking agents and their effect on cancer cells and normal lymphocytes
Chen, Wenbing,Balakrishnan, Kumudha,Kuang, Yunyan,Han, Yanyan,Fu, Min,Gandhi, Varsha,Peng, Xiaohua
, p. 4498 - 4510 (2014/07/07)
Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40-80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ～5 μM in CLL cells, while the IC 50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications.
Self-immolative nitrogen mustard prodrugs for suicide gene therapy
Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Friedlos, Frank,Martin, Janet,Spooner, Robert,Davies, Lawrence,Marais, Richard,Springer, Caroline J.
, p. 5297 - 5309 (2007/10/03)
Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1,6-elimination mechanism via an unstable intermediate. Thus, N-[(4-{[4-(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (23), N-[(4-{[4(bis{2- chloroethyl}amino)phenoxycarbonyloxy]methyl}phenoxy)carbonyl]-L-glutamic acid (30), N-[(4-{N-(4-(bis[2- chloroethyl]amino}}pheny)carbamoyloxy]methyl}phenoxy)carbonyl]-L-glutmic acid (37), and N-[(4-{[N-(4-{bis[2- chloroethyl]amino}phenyl)carbamoyloxy]methyl}phenyl)carbamoyl]-L-glutamic acid (40) were synthesized. They are bifunctional alkylating agents in which the activating effects of the phenolic hydroxyl or amino functions are masked through an oxycarbonyl or a carbamoyl bond to a benzylic spacer which is itself]inked to a glutamic acid by an oxycarbonyl or a carbamoyl bond. The corresponding fluoroethyl compounds 25, 32, 42, and 44 were also synthesized. The rationale was to obtain model compounds with greatly reduced alkylating abilities that would be much less reactive with nucleophiles compared to the corresponding chloroethyl derivatives. This enabled studies of these model compounds as substrates for CPG2, without incurring the rapid and complicated decomposition pathways of the chloroethyl derivatives. The prodrugs were desired to be activated to their corresponding phenol and aniline nitrogen mustard drugs by CPG2 for use in GDEPT. The synthesis of the analogous novel parent drugs (21b, 51) is also described. A colorectal cell line was engineered to express CPG2 tethered to the outer cell surface. The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ- expressing clones. The drugs released are up to 70-fold more potent than 4- [(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMBA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.
Glucuronide prodrugs of hydroxy compounds for antibody directed enzyme prodrug therapy (adept): A phenol nitrogen mustard carbamate
Schmidt,Florent,Monneret,Straub,Czech,Gerken,Bosslet
, p. 1071 - 1076 (2007/10/03)
A prodrug consisting of a β-D-glucuronic acid linked to a self-immolative spacer (a N-(ortho-hydroxyphenyl)-N-methylcarbamate) and a phenolic nitrogen mustard was synthesised. As this prodrug was easily cleaved by a β-glucuronidase enzyme and displayed lo
New mustard prodrugs for antibody-directed enzyme prodrug therapy: Alternatives to the amide link
Dowell, Robert I.,Springer, Caroline J.,Davies, David H.,Hadley, Elizabeth M.,Burke, Philip J.,Boyle, F. Thomas,Melton, Roger G.,Connors, Thomas A.,Blakey, David C.,Mauger, Anthony B.
, p. 1100 - 1105 (2007/10/03)
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 μM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
