A Platinum(IV) Prodrug—Perfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain

Abstract

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum­(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.

Perfluoroaryl and Perfluoroheteroaryl Reagents as Emerging New Tools for Peptide Synthesis, Modification and Bioconjugation

“…Decafluorobiphenyl (47) behaves similarly to hexafluorobenzene, undergoing a regioselective 4, 4'-double thiol-fluoride substitution (Scheme 11), and providing a longer crosslinking motif, well suited to i, i + 7 disulfide crosslinking. [30] Interestingly, the perfluoroaryl crosslinking of disulfides in transportan-10 [31] and Pt(IV) prodrug peptides for glioblastoma treatment [32] was also found to increase blood-brain barrier penetration in models, and may be utilised in future for improved targeting of notoriously challenging CNS targets.…”

Studies on the Synthesis of Perfluoroaryl Sulfides and their Application in Desulfurative Nickel-Catalyzed Reductive Cross-Coupling

“…Moreover, the scope of this defluorosulfurization could be broadened to disubstituted species by fine-tuning the reaction stoichiometry. Hexafluorobenzene (1ao) and octafluoronaphthalene (1ap) could react with two mercaptan groups and give a potential fixed and planar linker (3ao-3ap), [45][46][47] which could be furthermore applied to bioconjugation and materials chemistry.…”

“…In particular, the development of methods to introduce sulfur selectively into polyfluoroarenes is of growing importance, as polyfluoroaromatic sulfur-containing compounds are often encountered in pharmaceuticals (Scheme 1B), agrochemicals, and functional materials. [37][38][39][40] While recent developments have made polyfluoroaryl-sulfides synthetically accessible, [41][42][43][44][45][46][47] some reported synthetic processes still suffer from limitations, including poor regioselectivity. [41][42][43][44] Other strategies are rather complex and require the preparation of hetarenium salts for the synthesis.…”

“…[43][44] There are also other methods that have only been used in very focused settings, such as the preparation of polymers 45 and peptide stapling. [46][47] To deal with these issues, we attempted to develop a metal-free defluorosulfurization method for the synthesis of perfluoroarenes using SNAr chemistry, with a focus on the following considerations: 1) highly selective substitution of C−F bonds by mercaptans or thiolates; and 2) broad applicability with high functional group tolerance, making it suitable for the modification of complex molecules. In this report, we investigate the SNAr reactions of a broad spectrum of perfluoroarenes with mercaptans of varying electronic properties.…”

Theoretical Prediction and Explanation of Reaction Site Selectivity in the Addition of a Phenoxy Group to Perfluoropyrimidine, Perfluoropyridazine, and Perfluoropyrazine

“…Fluoropolymers, particularly those with fluoroaromatics in their architectures, are widely known for their desirable properties such as chemical resistance, thermal stability, and solution and melt processability [3][4][5][6]. Fluoroaromatics have also shown great promise for use in biomedical applications [7][8][9][10], including as substituents to allow medications to more easily cross the blood brain barrier [11,12] and penetrate cells [13].…”