ABSTRACT
It was shown for the first time that pentaamino acid derivative of fullerene C60 (potassium salt of fullerenylpenta-N-dihydroxytyrosine) affects three targets of type 2 diabetes mellitus. It competitively inhibits the enzymes aldose reductase and sorbitol dehydrogenase and also has an antiglycation effect on bovine serum albumin. The inhibition constants for these enzymes were calculated.
Subject(s)
Aldehyde Reductase/chemistry , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemistry , L-Iditol 2-Dehydrogenase/chemistry , Aldehyde Reductase/metabolism , Animals , Drug Evaluation, Preclinical , L-Iditol 2-Dehydrogenase/metabolism , MiceABSTRACT
We studied the effects of new water-soluble polysubstituted fullerene C60 (PFD) derivatives on activity of Ca2+-Mg2+ ATPase of the sarcoplasmic reticulum and cGMP phosphodiesterase. All examined fullerene derivatives inhibited activity of both enzymes. For instance, PFD-I, PFD-II, PFD-III, PFD-V, PFD-IX, PFD-X, and PFD-XI in a concentration of 5×10-5 M completely inhibited hydrolytic and transport functions of Ca2+-ATPase. These compounds in a concentration of 5×10-6 suppressed active transport of calcium ions by 51±5, 77±8, 52±5, 52±5, 100±10, 80±8, and 100±10%, respectively, and inhibited ATP hydrolysis by 31±3, 78±8, 18±2, 29±3, 78±8, 63±7, and 73±9%, respectively, uncoupling the hydrolytic and transport functions of the enzyme. PFD-I noncompetitive and reversibly reduced activity of Ca2+-ATPase (Ki=2.3×10-6 M). All the studied fullerene derivatives (except for PFD-VII) inhibited cGMP phosphodiesterase by more than 80% in concentration of 10-4 M and higher and by more than 50% in concentration of 10-5 M. PFD-I is a non-competitive reversible inhibitor of cGMP phosphodiesterase (Ki=7×10-6 M). These results allow us to expect antimetastatic, antiaggregatory, antihypertensive and vasodilative activity of the studied compounds.
Subject(s)
Ca(2+) Mg(2+)-ATPase/antagonists & inhibitors , Calcium/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Fullerenes/pharmacology , Sarcoplasmic Reticulum/drug effects , Adenosine Triphosphate/metabolism , Animals , Biological Transport, Active/drug effects , Ca(2+) Mg(2+)-ATPase/isolation & purification , Ca(2+) Mg(2+)-ATPase/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 6/isolation & purification , Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism , Fullerenes/chemistry , Hydrolysis , Ion Transport/drug effects , Kinetics , Muscle, Skeletal/chemistry , Rabbits , Sarcoplasmic Reticulum/chemistry , Sarcoplasmic Reticulum/enzymologyABSTRACT
Delivering drugs to the central nervous system (CNS) is a major challenge in treating CNS-related diseases. Nanoparticles that can cross blood-brain barrier (BBB) are potential tools. In this study, water-soluble C60 fullerene derivatives with different types of linkages between the fullerene cage and the solubilizing addend were synthesized (compounds 1-3: C-C bonds, compounds 4-5: C-S bonds, compound 6: C-P bonds, and compounds 7-9: C-N bonds). Fullerene derivatives 1-6 were observed to induce neural stem cell (NSC) proliferation in vitro and rescue the function of injured CNS in zebrafish. Fullerene derivatives 7-9 were found to inhibit glioblastoma cell proliferation in vitro and reduce glioblastoma formation in zebrafish. These effects were correlated with the cell metabolic changes. Particularly, compound 3 bearing residues of phenylbutiryc acids significantly promoted NSC proliferation and neural repair without causing tumor growth. Meanwhile, compound 7 with phenylalanine appendages significantly inhibited glioblastoma growth without retarding the neural repair. We conclude that the surface functional group determines the properties as well as the interactions of C60 with NSCs and glioma cells, producing either a neuroprotective or antitumor effect for possible treatment of CNS-related diseases.
