Premium
Cell Penetration, Herbicidal Activity, and in‐vivo ‐Toxicity of Oligo‐Arginine Derivatives and of Novel Guanidinium‐Rich Compounds Derived from the Biopolymer Cyanophycin
Author(s) -
Grogg Marcel,
Hilvert Donald,
Ebert MarcOlivier,
Beck Albert K.,
Seebach Dieter,
Kurth Felix,
Dittrich Petra S.,
Sparr Christof,
Wittlin Sergio,
Rottmann Matthias,
Mäser Pascal
Publication year - 2018
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201800112
Subject(s) - chemistry , biopolymer , arginine , in vivo , penetration (warfare) , biochemistry , biophysics , amino acid , organic chemistry , polymer , microbiology and biotechnology , biology , operations research , engineering
Oligo‐arginines are thoroughly studied cell‐penetrating peptides ( CPP s, Figures 1 and 2 ). Previous in‐vitro investigations with the octaarginine salt of the phosphonate fosmidomycin (herbicide and anti‐malaria drug) have shown a 40‐fold parasitaemia inhibition with P. falciparum , compared to fosmidomycin alone ( Figure 3 ). We have now tested this salt, as well as the corresponding phosphinate salt of the herbicide glufosinate, for herbicidal activity with whole plants by spray application, hoping for increased activities, i.e . decreased doses. However, both salts showed low herbicidal activity, indicating poor foliar uptake ( Table 1 ). Another pronounced difference between in‐vitro and in‐vivo activity was demonstrated with various cell‐penetrating octaarginine salts of fosmidomycin: intravenous injection to mice caused exitus of the animals within minutes, even at doses as low as 1.4 μmol/kg ( Table 2 ). The results show that use of CPP s for drug delivery, for instance to cancer cells and tissues, must be considered with due care. The biopolymer cyanophycin is a poly‐aspartic acid containing argininylated side chains ( Figure 4 ); its building block is the dipeptide H‐ β Asp‐ α Arg‐ OH (H‐Adp‐ OH ). To test and compare the biological properties with those of octaarginines we synthesized Adp 8 ‐derivatives ( Figure 5 ). Intravenouse injection of H‐Adp 8 ‐ NH 2 into the tail vein of mice with doses as high as 45 μmol/kg causes no symptoms whatsoever ( Table 3 ), but H‐Adp 8 ‐ NH 2 is not cell penetrating ( HEK 293 and MCF ‐7 cells, Figure 6 ). On the other hand, the fluorescently labeled octamers FAM ‐(Adp( OM e)) 8 ‐ NH 2 and FAM ‐(Adp( NM e 2 )) 8 ‐ NH 2 with ester and amide groups in the side chains exhibit mediocre to high cell‐wall permeability ( Figure 6 ), and are toxic ( Table 3 ). Possible reasons for this behavior are discussed ( Figure 7 ) and corresponding NMR spectra are presented ( Figure 8 ).