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 μM fully suppress and between 20–100 μM reduce proliferation of the human melanoma cell line. In concentration 20 μM 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 μM 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.
Highlights
Since the first report by Tomalia et al, on synthesis of polyamidoamine dendrimers (PAMAM), these branched polyfunctional polymers with well-defined structure have received a lot of scientific attention due to the prospective high potential in a wide range of medical applications [1,2].High demand for innovative drugs with the high therapeutic index and negligible side effects directed pharmaceutical research into formulation of the known bioactive molecules with safe, site-specific carrier systems
While the DPPH assay shows the capacity of antioxidant to transfer electrons, the ABTS assay determines cationic free radical scavenging activity involving both electron and hydrogen transfer mechanisms
Each of the studied dendrimers contains in their structure several chemical groups that might evoke toxicity in the living cells with less impact on the in vitro laboratory testing
Summary
Since the first report by Tomalia et al, on synthesis of polyamidoamine dendrimers (PAMAM), these branched polyfunctional polymers with well-defined structure have received a lot of scientific attention due to the prospective high potential in a wide range of medical applications [1,2].High demand for innovative drugs with the high therapeutic index and negligible side effects directed pharmaceutical research into formulation of the known bioactive molecules with safe, site-specific carrier systems. Recent studies confirmed that the presence of free radicals initiates undesired processes, e.g. carcinogenesis or degeneration of cells constituting nervous system [8,9]. In this respect, the response of biological molecules toward oxidizing conditions and knowledge of natural compounds repairing abrogated metabolic pathways is of continuing interest. The potential toxicity of the redox-active nanomaterials has been the subject of much concern in a two-fold context: by undesired disturbance of the metabolic pathways [10,11,12] and on the other side, for the possibility of application of these processes in therapy of various diseases (e.g. as reactive oxygen species (ROS)-inducing drugs) [13,14,15]. 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
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