Current Medicinal Chemistry - Volume 22, Issue 36, 2015

L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational modification of the amino acid tyrosine. L-DOPA is modified during metabolism to catecholamine neurotransmitters, noradrenaline and adrenaline, which are characterized by different biological activities. L-DOPA has been the first drug of choice in the therapy of Parkinson’s disease that is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons of substantia nigra pars compacta. The social and economic impact of these diseases is very high due to the progressive aging of the population. This review focuses on the biological effect of LDOPA, as well as on the synthesis of L-DOPA derivatives and their application in central nervous system diseases. Among them, L-DOPA-containing peptides (L-DOPA-Pep) show important biological and pharmacological activities. For example, L-DOPA analogues of the alpha-factor interact with models of the G proteincoupled receptor, inhibit the oxidation of low-density lipoproteins, and are used for improving L-DOPA absorption in long-term treatment of Parkinson’s disease and as skin moisturizer in cosmetic compositions. Moreover, L-DOPA residues in proteins provide reactive tools for the preparation of adhesives and coatings materials. Usually, L-DOPA-Pep is prepared by traditional liquid or solid state procedures starting from simple amino acids. Recently, selective side-chain modifications of pre-formed peptides have also been reported both for linear and branched peptides. Here, we describe the recent advances in the synthesis of L-DOPA and dopa-peptidomimetics and their biological and pharmacological activities, focusing the attention on new synthetic procedures and biological mechanism of actions.

Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) composed of alternating N-acetyl galactosamine and glucuronic acid units within disaccharide building blocks. CS is a key functional component in proteoglycans of cartilaginous tissues. Owing to its numerous biological roles, CS is widely explored in the pharmaceutical market as nutraceutical ingredient commonly utilized against arthritis, osteoarthrosis, and sometimes osteoporosis. Tissues like shark cartilage and bovine trachea are common sources of CS. Nonetheless, a new CS type has been introduced and investigated in the last few decades in what regards its medical potentials. It is named fucosylated chondroitin sulfate (FucCS). This less common CS type is isolated exclusively from the body wall of sea cucumbers. The presence of fucosyl branching units in the holothurian FucCS gives to this unique GAG, therapeutic properties in various pathophysiological systems which are inexistent in the common CS explored in the market. Examples of these systems are coagulation, thrombosis, hemodialysis, atherosclerosis, cellular growth, angiogenesis, fibrosis, tumor growth, inflammation, viral and protozoan infections, hyperglycemia, diabetes-related pathological events and tissue damage. This report aims at describing the medical benefits gained upon fucosylation of CS. Clinical prospects of these medical benefits are also discussed herein.

Colchicine has recently gained considerable attention in the field of cardiovascular research, after a number of studies showed that it may be of use in several settings of cardiovascular disease, including chronic coronary artery disease and following stent implantation. Its unique anti-inflammatory mechanism of action makes it safe to use in patients with cardiovascular disease, unlike most – if not all – currently available antiinflammatory agents. While its prophylactic and therapeutic value is well-established in certain conditions involving an acute inflammatory response, e.g. pericarditis, in other conditions, including coronary artery disease and heart failure, which are associated with a chronic low-grade inflammatory state, the evidence regarding its potential use remains sparse. In this concise review, we present key features of this drug and the rationale for colchicine therapy, in the context of acute and chronic coronary artery disease, as well as in ischemic heart failure and critically examine the evidence concerning a possible future role of colchicine treatment in these conditions.

As a significant tumor feature, hypoxia can trigger cancer adaptive processes, induce malignant phenotype development, and promote drug resistance. Previous studies demonstrated that exosomes are critical during these procedures. Exosomes are small vesicles formed in vesicular bodies in the endosomal network. These small vesicles are mainly involved in the transport of bioactive molecules between cells. Exosomes are also involved in the mediation of some cellular communications depending on derived donor cells; thus, recipient cells undergo phenotypic changes. Furthermore, hypoxia can remarkably stimulate exosomal secretion; for instance, nucleic acids and proteins as transmission signals in exosomes in a tumor microenvironment are involved in various functions, such as inducing intratumoral heterogeneity, altering immunological responses, producing cancer-associated fibroblasts, and promoting angiogenesis and metastasis. Moreover, exosome contents resemble those of a donor cell; this finding indicates that exosomes may also be regarded as suitable biomarkers of hypoxia status. Therefore, exosomes can be used to facilitate diagnosis and prognosis with minimal invasive procedures. Further studies on exosomes in cancer may provide new therapeutic strategies.

Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biological activities. One of the most interesting properties of curcumin (1) is the antitumour activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivatives have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivatives have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable α,β-unsaturated diketone linker present in curcumin (1) may not be necessary for the antitumour activity; generally, shorter linkers result in more potent compounds than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biological activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clinical trials. This article aims to review the synthesis and biological activities of curcumin (1) and derivatives, highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compound for the development of new anticancer drugs.