113942-30-6Relevant articles and documents
Antitumor imidazotetrazines. 41.1 Conjugation of the antitumor agents mitozolomide and temozolomide to peptides and lexitropsins bearing DNA major and minor groove-binding structural motifs
Arrowsmith, Jill,Jennings, Sharon A.,Clark, Alan S.,Stevens, Malcolm F. G.
, p. 5458 - 5470 (2002)
Carboxylic acids derived from the amido groups of the antitumor agents mitozolomide and temozolomide have been conjugated to simple amino acids and peptides by carbodiimide coupling. Solid-state peptide synthesis has been applied to link the acids to DNA major groove-binding peptidic motifs known to adopt α-helical conformations. Attachment of the acids to pyrrole and imidazole polyamidic lexitropsins gave a series of potential DNA minor groove-binding ligands. In vitro biological evaluation of a limited number of these novel conjugates failed to demonstrate any enhanced growth-inhibitory activity compared to the unconjugated drugs; sites of alkylation at tracts of multiple guanines were also unaffected. Attachment of additional residues at C-8 of the imidazotetrazines did not perturb the chemistry of activation of the bicyclic nucleus, and biological sequelae can be rationalized by invoking the liberation of a common, diffusible, reactive chemical intermediate, the methanediazonium ion.
Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- A nd 3D-Spheroid-Based in Vitro Platforms
Baranyai, Zsuzsa,Biri-Kovács, Beáta,Krátky, Martin,Szeder, Bálint,Debreczeni, Márta L.,Budai, Johanna,Kovács, Bence,Horváth, Lilla,Pári, Edit,Németh, Zsuzsanna,Cervenak, László,Zsila, Ferenc,Méhes, El?d,Kiss, éva,Vin?ová, Jarmila,B?sze, Szilvia
, p. 2982 - 3005 (2021)
Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.
Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
Bandolik, Jan J.,Bhatia, Sanil,Borkhardt, Arndt,Hamacher, Alexandra,Hansen, Finn K.,Kassack, Matthias U.,Meiler, Jens,Roatsch, Martin,S?nnichsen, Melf,Sch?ler, Andrea,Schoeder, Clara T.,Sinatra, Laura
supporting information, p. 22494 - 22499 (2020/10/12)
Inhibition of more than one cancer-related pathway by multi-target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well-established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore-linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid-phase-supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ-H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof-of-concept proteolysis-targeting chimera (PROTAC), which efficiently degrades histone deacetylases.
Temozolomide prodrug nano-micelles and preparation method therefor and application of temozolomide prodrug nano-micelles
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Paragraph 0036-0040, (2020/06/20)
Temozolomide prodrug nano-micelles each comprise a hydrophilic shell and a hydrophobic core; each hydrophilic shell is polyoxazoline or polyethylene glycol, and the hydrophobic cores are each polytemozolomide. A preparation method for the temozolomide prodrug nano-micelles is characterized in that the polyoxazoline or polyethylene glycol reacts with 4-cyano-4-valeric acid through an esterificationreaction, and as a macromolecular reversible addition-fragmentation chain transfer polymerization (RAFT) reagent, an obtained product reacts with temozolomide-methyl methacrylate under catalysis of azodiisobutyronitrile to obtain amphiphilic block polymers. According to the temozolomide prodrug nano-micelles, the amphiphilic block polymers can extend the half-life period of temozolomide; two amphiphilic block polymer nano-micelles both belong to the prodrugs of the temozolomide, and meanwhile, the cores of the micelles can entrap other anticancer drugs to realize combination therapy of different drugs. After entering a tumor cell, the polyoxazoline-polytemozolomide micelles crack in the acidic environment of the cancer cell, and encapsulated drugs are quickly released, and thereby, a high-efficiency therapeutic effect is generated, and the problems that a drug carrier is slow in drug release, and is prone to be drug-resistant are solved.
