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Cell penetration, herbicidal activity, and in-vivo-toxicity of oligo-arginine derivatives and of novel guanidinium-rich compounds derived from the biopolymer cyanophycin Grogg, Marcel and Hilvert, Donald and Ebert, Marc-Olivier and Beck, Albert K. and Seebach, Dieter and Kurth, Felix and Dittrich, Petra S. and Sparr, C. and Wittlin, Sergio and Rottmann, Matthias and Mäser, Pascal

Grogg, Marcel and Hilvert, Donald and Ebert, Marc-Olivier and Beck, Albert K. and Seebach, Dieter and Kurth, Felix and Dittrich, Petra S. and Sparr, Christof and Wittlin, Sergio and Rottmann, Matthias and Mäser, Pascal. (2018) Cell penetration, herbicidal activity, and in-vivo-toxicity of oligo-arginine derivatives and of novel guanidinium-rich compounds derived from the biopolymer cyanophycin Grogg, Marcel and Hilvert, Donald and Ebert, Marc-Olivier and Beck, Albert K. and Seebach, Dieter and Kurth, Felix and Dittrich, Petra S. and Sparr, C. and Wittlin, Sergio and Rottmann, Matthias and Mäser, Pascal. Helvetica Chimica Acta, 101 (10). e1800112.

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Abstract

Oligo‐arginines are thoroughly studied cell‐penetrating peptides (CPPs, 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 CPPs 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‐βAsp‐αArg‐OH (H‐Adp‐OH). To test and compare the biological properties with those of octaarginines we synthesized Adp8‐derivatives (Figure 5). Intravenouse injection of H‐Adp8‐NH2 into the tail vein of mice with doses as high as 45 μmol/kg causes no symptoms whatsoever (Table 3), but H‐Adp8‐NH2 is not cell penetrating (HEK293 and MCF‐7 cells, Figure 6). On the other hand, the fluorescently labeled octamers FAM‐(Adp(OMe))8‐NH2 and FAM‐(Adp(NMe2))8‐NH2 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).
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio and Rottmann, Matthias and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:0018-019X
e-ISSN:1522-2675
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:09 Jul 2019 12:44
Deposited On:15 Nov 2018 15:30

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