Synthesis of Artesunic Acid-Coumarin Hybrids as Potential Antimelanoma Agents.

Current therapy against melanoma relies on surgical treatment or, in alternative, on conventional drug therapy. Often these therapeutic agents are ineffective due to the development of resistance phenomena. For this purpose, chemical hybridization emerged as an effective strategy to overcome the development of drug resistance. In this study, a series of molecular hybrids were synthesized combining the sesquiterpene artesunic acid with a panel of phytochemical coumarins. Cytotoxicity, antimelanoma effect, and cancer selectivity of the novel compounds were evaluated by MTT assay on primary and metastatic cells and on healthy fibroblasts as a reference. The two most active compounds showed lower cytotoxicity and higher activity against metastatic melanoma than paclitaxel and artesunic acid. Further tests, including cellular proliferation, apoptosis, confocal microscopy, and MTT analyses in the presence of an iron chelating agent, were conducted with the aim of tentatively addressing the mode of action and the pharmacokinetic profile of selected compounds.

A Photochemoenzymatic Hunsdiecker-Borodin-Type Halodecarboxylation of Ferulic Acid.

A photochemoenzymatic halodecarboxylation of ferulic acid was achieved using vanadate-dependent chloroperoxidase as (bio)catalyst and oxygen and organic solvent as sole stoichiometric reagents in a biphasic system. Performance and selectivity were improved through a phase transfer catalyst, reaching a turnover number of 660.000 for the enzyme.

Lignin Nanoparticles Deliver Novel Thymine Biomimetic Photo-Adducts with Antimelanoma Activity.

We report here the synthesis of novel thymine biomimetic photo-adducts bearing an alkane spacer between nucleobases and characterized by antimelanoma activity against two mutated cancer cell lines overexpressing human Topoisomerase 1 (TOP1), namely SKMEL28 and RPMI7951. Among them, Dewar Valence photo-adducts showed a selectivity index higher than the corresponding pyrimidine-(6-4)-pyrimidone and cyclobutane counterpart and were characterized by the highest affinity towards TOP1/DNA complex as evaluated by molecular docking analysis. The antimelanoma activity of novel photo-adducts was retained after loading into UV photo-protective lignin nanoparticles as stabilizing agent and efficient drug delivery system. Overall, these results support a combined antimelanoma and UV sunscreen strategy involving the use of photo-protective lignin nanoparticles for the controlled release of thymine dimers on the skin followed by their sacrificial transformation into photo-adducts and successive inhibition of melanoma and alert of cellular UV machinery repair pathways.

Multicomponent Reactions in the Synthesis of Antiviral Compounds.

BACKGROUND: Multicomponent reactions are one-pot processes for the synthesis of highly functionalized hetero-cyclic and hetero-acyclic compounds, often endowed with biological activity. OBJECTIVE: Multicomponent reactions are considered green processes with a high atom economy. In addition, they present advantages compared to the classic synthetic methods, such as high efficiency and low waste production. METHODS: In these reactions, two or more reagents are combined together in the same flask to yield a product containing almost all the atoms of the starting materials. RESULTS: The scope of this review is to present an overview of the application of multicomponent reactions in the synthesis of compounds endowed with antiviral activity. The syntheses are classified depending on the viral target. CONCLUSION: Multicomponent reactions can be applied to all the stages of the drug discovery and development process, making them very useful in the search for new agents active against emerging (viral) pathogens.

Dendrimeric Structures in the Synthesis of Fine Chemicals.

Dendrimers are highly branched structures with a defined shape, dimension, and molecular weight. They consist of three major components: the central core, branches, and terminal groups. In recent years, dendrimers have received great attention in medicinal chemistry, diagnostic field, science of materials, electrochemistry, and catalysis. In addition, they are largely applied for the functionalization of biocompatible semiconductors, in gene transfection processes, as well as in the preparation of nano-devices, including heterogeneous catalysts. Here, we describe recent advances in the design and application of dendrimers in catalytic organic and inorganic processes, sustainable and low environmental impact, photosensitive materials, nano-delivery systems, and antiviral agents' dendrimers.

Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid.

A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC50 >300 µM) and high antimelanoma activity (IC50 =0.05 µM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.

Laccase-Catalyzed 1,4-Dioxane-Mediated Synthesis of Belladine N-Oxides with Anti-Influenza A Virus Activity.

Belladine N-oxides active against influenza A virus have been synthetized by a novel laccase-catalyzed 1,4-dioxane-mediated oxidation of aromatic and side-chain modified belladine derivatives. Electron paramagnetic resonance (EPR) analysis confirmed the role of 1,4-dioxane as a co-oxidant. The reaction was chemo-selective, showing a high functional-group compatibility. The novel belladine N-oxides were active against influenza A virus, involving the early stage of the virus replication life cycle.

Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity in vitro. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. In silico molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.

Synthesis and Evaluation of Artemisinin-Based Hybrid and Dimer Derivatives as Antimelanoma Agents.

A library of hybrid and dimer compounds based on the natural scaffold of artemisinin was synthesized. These derivatives were obtained by coupling of artemisinin derivatives, artesunate, and dihydroartemisinin with a panel of phytochemical compounds. The novel artemisinin-based hybrids and dimers were evaluated for their anticancer activity on a cervical cancer cell line (HeLa) and on three complementary metastatic melanoma cancer cell lines (SK-MEL3, SK-MEL24, and RPMI-7951). Two hybrid compounds obtained by coupling of artesunate with eugenol and tyrosol, and one of the dimer compounds containing curcumin, emerged as the most active and cancer-selective derivatives.

Biomimetic synthesis of galantamine via laccase/TEMPO mediated oxidative coupling.

Laccase-mediated intramolecular oxidative radical coupling of N-formyl-2-bromo-O-methylnorbelladine afforded a novel and isolable spirocyclohexadienonic intermediate of galantamine. High yield and conversion of substrate were obtained in the presence of the redox mediator 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). This laccase procedure, with an overall yield of 34%, represents a scalable and environmentally friendly alternative to previously reported syntheses of galantamine based on the use of potassium ferricyanide as an unspecific radical coupling reagent.