Aiming at the tumor-specific accumulation of MGMT-inhibitors

• Verfasst von: Wängler, Björn [VerfasserIn]
• Verfasst von: Schirrmacher, Ralf [VerfasserIn]
• Verfasst von: Wängler, Carmen [VerfasserIn]
• Titel: Aiming at the tumor-specific accumulation of MGMT-inhibitors
• Titelzusatz: First description of a synthetic strategy towards inhibitor-peptide conjugates
• Verf.angabe: Bjoern Waengler, Ralf Schirrmacher, Carmen Waengler
• E-Jahr: 2020
• Jahr: 12 March 2020
• Umfang: 4 S.
• Fussnoten: Gesehen am 27.05.2020
• Titel Quelle: Enthalten in: Tetrahedron letters
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1959
• Jahr Quelle: 2020
• Band/Heft Quelle: 61(2020,19) Artikel-Nummer 151840, 4 Seiten
• ISSN Quelle: 1873-3581
• DOI: doi:10.1016/j.tetlet.2020.151840
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Adjuvants to alkylating therapy
• Sach-SW: alkyltransferase
• Sach-SW: derivatives
• Sach-SW: glucose transporters
• Sach-SW: inactivation
• Sach-SW: MGMT inhibitor
• Sach-SW: o-6-methylguanine-dna methyltransferase
• Sach-SW: Peptide conjugates
• Sach-SW: receptor
• Sach-SW: Tumor targeting
• K10plus-PPN: 1698894899

Abstract

In the therapy of cancer, alkylating agents are an efficient and often-used substance class. However, cells can repair the resulting alkyl modifications in the O-6-position of guanine using the repair protein methylguanine methyltransferase (MGMT), giving rise to resistance and inefficient therapy. A possibility to overcome this resistance is the use of MGMT inhibitors as adjuvants to alkylating therapies. However, MGMT inhibitors also sensitize healthy cells towards alkylating therapies. A strategy to circumvent this is the development of tumor-specific inhibitors which could be based on peptidic ligands as carriers. Such constructs would enable a receptor-specific uptake into tumors. Furthermore, the MGMT inhibitors could be adapted to the respective tumor entity by changing the peptide carrier. However, no peptide-based tumor-specific MGMT inhibitors were described so far. Thus, we have developed a synthetic strategy to obtain covalent conjugates of receptor-specific peptides and O-6-benzylguanine derivatives. As model compounds, the MGMT inhibitor O-6-(3-bromobenzyl)guanine and the receptor-specific peptides c (RGDfK), TATE, PESIN, neurotensin-2656 and minigastrin-9 were chosen and successfully assembled to obtain potentially tumor-specific MGMT inhibitors. Both, the O-6-(3-bromobenzyl)guanine as well as the peptide derivatives are easily replaceable during the syntheses to tailor peptide-based bioconjugates adaptable to the specific tumor entity. (C) 2020 Elsevier Ltd. All rights reserved.