L-Dopa− and Dopamine−(R)-α-Lipoic Acid Conjugates as Multifunctional Codrugs with Antioxidant Properties

Abstract

A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain.

UPEI-400, a Conjugate of Lipoic Acid and Scopoletin, Mediates Neuroprotection in a Rat Model of Ischemia/Reperfusion

“…Covalent linkage of LA with ibuprofen has been demonstrated to be neuroprotective in rodent models of Alzheimer's disease where administration of the co-drug decreased the oxidative damage due to the infusion of Aβ (1-40) [10]. Also, a co-drug produced by chemically linking LA with L-dopa or dopamine decreased neuronal oxidative damage associated with the administration of L-dopa or dopamine on their own [53].…”

Novel screening assay for antioxidant protection against peroxyl radical‐induced loss of protein function

“…The antioxidant capacity of three COMT inhibitors bearing a nitrocatecholic structure, nitecapone (11), entacapone (12), and tolcapone (13) (Fig. 1) to protect proteins from peroxyl radical-induced damage was studied using the screening assay developed.…”

“…9,10 Multifunctional drugs with antioxidant properties might thus well be the answer to complex diseases implicating free radical-induced damage to biotargets. Multifunctional compounds with antioxidant properties are already being developed and their activity against various diseases, such as cancer, 11,12 neurodegenerative, [13][14][15][16][17][18] or cardiovascular diseases, 9,10,19,20 has been established.…”

“…Quercetin dihydrate (1), mangiferin (4), resveratrol (5), mannitol (9), and glutathione (10) were from Sigma-Aldrich (Buchs, Switzerland). Tolcapone (11), entacapone (12), and nitecapone (13) were kindly donated by Prof. Alberto Gasco (Dipartimento della Scienza e tecnologia del Farmaco, University of Turin, Italy). Methanol of HPLC grade was from Prolabo (Fontenay-sous-Bois, France), and ethanol was obtained from Schweizerhalle Chemie AG (Basel, Switzerland).…”

Development of Selective Butyrylcholinesterase Inhibitors Using (R)-Lipoic Acid-Polyphenol Hybrid Molecules

“…ALA-L-dopa and ALA-dopamine, 21 ALA-Trolox (a water-soluble analogue of vitamin E), 22 ALA-amphiphilic hybrid of α-phenyl-N-tert-butyl nitrone (PBN) (PBNLP), 23 ALA-nitric oxide synthase inhibitors, 24 and ALA-N-alkyl-substituted morpholine, 25 ALA-chroman analogues, 26 ALA-quinazolinimines, 27 and ALA-quinazolinimines 28 have been synthesized. Polyphenols (PPs) are known as a natural antioxidant due to reduce reactive oxygen species levels in vivo.…”