Molecular Antioxidant Properties and In Vitro Cell Toxicity of the p-Aminobenzoic Acid (PABA) Functionalized Peptide Dendrimers §

Abstract

Background: Exposure to ozone level and ultraviolet (UV) radiation is one of the major concerns in the context of public health. Numerous studies confirmed that abundant free radicals initiate undesired processes, e.g. carcinogenesis, cells degeneration, etc. Therefore, the design of redox-active molecules with novel structures, containing radical quenchers molecules with novel structures, and understanding their chemistry and biology, might be one of the prospective solutions. Methods: We designed a group of peptide dendrimers carrying multiple copies of p-aminobenzoic acid (PABA) and evaluated their molecular antioxidant properties in 1,1’-diphenyl-2-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests. Cytotoxicity against human melanoma and fibroblast cells as well as against primary cerebral granule cells (CGC) alone and challenged by neurotoxic sodium glutamate and production of reactive oxygen species (ROS) in presence of dendrimers were measured. Results: PABA-terminated dendrimers express enhanced radical and radical cation scavenging properties in relation to PABA alone. In cellular tests, the dendrimers at 100 M fully suppress and between 20–100 M reduce proliferation of the human melanoma cell line. In concentration 20 M dendrimers generate small amount of the reactive oxygen species (<25%) but even in their presence human fibroblast and mouse cerebellar granule cells remain intact Moreover, dendrimers at 0.2–20 µM concentration (except one) increased the percentage of viable fibroblasts and CGC cells treated with 100 M glutamate. Conclusions: Designed PABA-functionalized peptide dendrimers might be a potential source of new antioxidants with cationic and neutral radicals scavenging potency and/or new compounds with marked selectivity against human melanoma cell or glutamate-stressed CGC neurons. The scavenging level of dendrimers depends strongly on the chemical structure of dendrimer and the presence of other groups that may be prompted into radical form. The present studies found different biological properties for dendrimers constructed from the same chemical fragments but the differing structure of the dendrimer tree provides once again evidence that the structure of dendrimer can have a significant impact on drug–target interactions.

Bioinspired Bola-Type Peptide Dendrimers Inhibit Proliferation and Invasiveness of Glioblastoma Cells in a Manner Dependent on Their Structure and Amphipathic Properties

“…Since the production of AMP’s in large quantities is still problematic, we designed several series of AMP’ mimetics in the form of amphiphilic branched peptides (dendrimers or dendrons) to show their significant activity against bacteria [ 24 , 25 ], fungi [ 26 , 27 , 28 ], melanoma [ 29 ] and glioblastoma cells [ 30 ]. The branched structure facilitated the localization/exposition of multiple side chains of amino acids and other groups on their molecular surface.…”

4-Aminobenzoic Acid Derivatives: Converting Folate Precursor to Antimicrobial and Cytotoxic Agents

“…In addition to PABA "non-imine" cytotoxic derivatives [1,5,12,44], Farooq et al [18] discovered N-alkylisatin-3-iminobenzoic acids, i.e., Schiff bases of substituted isatin and PABA, as potential cytotoxic/antileukemic agents with IC 50 for human normal as well as cancer cell lines comparable to our the most active molecules. Thus, the formation of Schiff bases could convert non-toxic PABA to moderate cytotoxic agents, depending on the carbonyl compound used.…”

“…However, PABA is neither essential nor biosynthesized in mammals. It is produced by symbiotic bacteria, especially Escherichia coli and absorbed from dietary intake [1][2][3][4][5].…”

“…PABA has been linked with other bioactive scaffolds involving NH 2 group via amide bond [15], as a secondary amine [1] or ureido moiety [16]. The derivatives of PABA showed improved radical scavenging properties and also enhanced toxicity for cancer cells [5]. PABA-ambazone salt exhibited improved antibacterial effect when compared to parent drugs [17].…”

Peptide Dendrimers with Non-Symmetric Bola Structure Exert Long Term Effect on Glioblastoma and Neuroblastoma Cell Lines

“…Cytotoxic effect was potentiated when dendrimers contained indole residue at C-terminal position. On the other hand, peptide dendrimers functionalized with p -aminobenzoic acid (PABA) expressed activity against human melanoma cell line, playing also protective role in neurons [ 14 ]. Therefore, we hypothesized that lower neurotoxicity of the latter was associated with antioxidant and reactive oxygen species (ROS) scavenging properties that are known attributes of PABA and indole moieties [ 15 , 16 ].…”