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.
Solid lipid nanoparticles carrying temozolomide for melanoma treatment. Preliminary in vitro and in vivo studies
Clemente, Nausicaa,Ferrara, Benedetta,Gigliotti, Casimiro Luca,Boggio, Elena,Capucchio, Maria Teresa,Biasibetti, Elena,Schiffer, Davide,Mellai, Marta,Annovazzi, Laura,Cangemi, Luigi,Muntoni, Elisabetta,Miglio, Gianluca,Dianzani, Umberto,Battaglia, Luigi,Dianzani, Chiara
, (2018)
Aim: To develop an innovative delivery system for temozolomide (TMZ) in solid lipid nanoparticles (SLN), which has been preliminarily investigated for the treatment of melanoma. Materials and Methods: SLN-TMZ was obtained through fatty acid coacervation. Its pharmacological effects were assessed and compared with free TMZ in in vitro and in vivo models of melanoma and glioblastoma. Results: Compared to the standard free TMZ, SLN-TMZ exerted larger effects, when cell proliferation of melanoma cells, and neoangiogeneis were evaluated. SLN-TMZ also inhibited growth and vascularization of B16-F10 melanoma in C57/BL6 mice, without apparent toxic effects. Conclusion: SLN could be a promising strategy for the delivery of TMZ, allowing an increased stability of the drug and thereby its employment in the treatment of aggressive malignacies.
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.
IMIDAZOTETRAZINE COMPOUNDS
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Page/Page column 39, (2020/03/02)
New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.
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.
A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression
Ingham, Oliver,Shervington, Amal,Shervington, Leroy
, p. 17561 - 17570 (2020/06/19)
The standard of care treatment for patients diagnosed with glioblastoma multiforme (GBM) is temozolomide (TMZ). Tumour resistance to TMZ results in significantly limited clinical effectiveness. There is therefore an inherent need for alternatives to TMZ capable of overcoming resistance associated with MGMT and MMR. In the present study, a series of ester and amide analogues of TMZ, modified at position 8 on the imidazole ring, were prepared and investigated for antiproliferative properties. It was found that phenolic ester analogues of TMZ displayed increased potency, of up to 5-fold, against specified glioblastoma cell lines. The encouraging results displayed by the phenolic TMZ esters prompted further investigations against patient-derived primary glioblastoma cultures. The primary cultures, BTNW914 and BTNW374, were MGMT positive and MGMT negative, respectively. Lead phenolic TMZ esters were found to decrease viability in primary cells at clinically relevant concentrations, irrespective of MGMT expression. Furthermore, TMZ was found to be ineffective against the same primary cells at clinically relevant concentrations. The novel phenyl ester analogues of TMZ, described in this study, could have potential chemotherapeutic properties for the treatment of GBM, overcoming the resistance associated with the expression of MGMT.
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.
Temozolomide polymer prodrug and its preparation method and application (by machine translation)
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Paragraph 0025; 0026, (2019/11/13)
Temozolomide polymer prodrug and its preparation method and application, including: the end of the synthesis of hydrophilic polymer is hydroxy; synthetic terminal group is carboxyl derivatives of temozolomide; through the hydrophilic polymer end of temozolomide derivatives of hydroxyl and carboxyl reaction, the temozolomide is bonded to the end of the hydrophilic polymer, shall temozolomide polymer prodrugs. The invention of temozolomide polymeric prodrugs, temozolomide is connected with the polymer by a covalent bond, can be kept stable in vivo circulation; temozolomide with polymer through covalent bond can be connected after the in water to form nano micelle, this nano micelle in extracellular and not easy to cleavage in the blood, the temozolomide is easy to be degraded under physiological conditions at the same time overcome the problem of the medicament in the body is easy to be leakage, cycle time and short. (by machine translation)
Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma
Svec, Riley L.,Furiassi, Lucia,Skibinski, Christine G.,Fan, Timothy M.,Riggins, Gregory J.,Hergenrother, Paul J.
, p. 3206 - 3216 (2018/11/30)
Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.
TEMOZOLOMIDE COMPOUNDS, POLYMERS PREPARED THEREFROM, AND METHOD OF TREATING A DISEASE
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Paragraph 0082; 0101-0102, (2018/04/13)
A temozolomide compound according to formula (I) is described, wherein R1, L1, and X are defined herein. The temozolomide compound can be used to prepare polymers comprising temozolomide. Additionally, the polymers comprising temozolomide can be particularly useful in the treatment of certain diseases.
