Ángel Amesty

Synthesis and study of antiproliferative, antitopoisomerase II, DNA-intercalating and DNA-damaging activities of arylnaphthalimides

A series of arylnaphthalimides were designed and synthesized to overcome the dose-limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafides biological activities.

Benzodihydrofurans from Cyperus teneriffae.

Three new benzodihydrofurans (1-3) and seven known aromatic compounds (4-10) were isolated from the roots of Cyperus teneriffae. Vibrational circular dichroism spectroscopy was used to define the absolute configuration of 1.

Synthesis and biological evaluation of naphthoquinone-coumarin conjugates as topoisomerase II inhibitors

Based on previous Topoisomerase II docking studies of naphthoquinone derivatives, a series of naphthoquinone-coumarin conjugates was synthesized through a multicomponent reaction from aromatic aldehydes, 4-hydroxycoumarin and 2-hydroxynaphthoquinone. The hybrid structures were evaluated against the α isoform of human topoisomerase II (hTopoIIα), Escherichia coli DNA Gyrase and E. coli Topoisomerase I. All tested compounds inhibited the hTopoIIα-mediated relaxation of negatively supercoiled circular DNA in the low micromolar range. This inhibition was specific since neither DNA Gyrase nor Topoisomerase I were affected. Cleavage assays pointed out that naphthoquinone-coumarins act by catalytically inhibiting hTopoIIα. ATPase assays and molecular docking studies further pointed out that the mode of action is related to the hTopoIIα ATP-binding site.

Synthesis and Antimicrobial Activity of 4-Substituted 1,2,3-Triazole-Coumarin Derivatives

A new series of coumarin-1,2,3-triazole conjugates with varied alkyl, phenyl and heterocycle moieties at C-4 of the triazole nucleus were synthesized using a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated coumarin (3) or N-propargylated coumarin (6) with alkyl or aryl azides. Based on their minimal inhibitory concentrations (MICs) against selected microorganisms, six out of twenty-six compounds showed significant antibacterial activity towards Enterococcus faecalis (MIC = 12.5–50 µg/mL). Moreover, the synthesized triazoles show relatively low toxicity against human erythrocytes.

5-Ethynylarylnaphthalimides as antitumor agents: Synthesis and biological evaluation

A set of 5-ethynylarylnaphthalimides was synthesized by Sonogashira cross-coupling reactions and evaluated for antiproliferative and antitopoisomerase II in vitro activities. Furthermore docking studies of these molecules as DNA-intercalators were carried out and the in vivo DNA-damaging activity was also determined with the model organism Saccharomyces cerevisiae. From the obtained results three naphthalimides 6, 13 and 14 showed strong topoisomerase II inhibitory activity. These three molecules also presented good docking scores as DNA-intercalators using a self-complementary oligodeoxynucleotide d(ATGCAT)2 as a model, and compounds 13 and 14 were among the most cytotoxic in the in vivo DNA-damaging activity.

Synthesis of 4,4'-Diaminotriphenylmethanes with Potential Selective Estrogen Receptor Modulator (SERM)-like Activity.

In this study, a series of new 4,4′‐diaminotriphenylmethanes was efficiently synthesized from aromatic aldehydes and 2,5‐dimethoxybenzenamine under microwave irradiation in the presence of Sc(OTf)3 as a catalyst. Antiproliferative activity was assessed by using the MCF‐7 estrogen receptor (ER)‐positive breast cancer cell line, and antagonist/agonist transcriptional activities were determined. Docking studies and competition studies of triphenylmethanes and radiolabeled estradiol determined that these compounds do not bind the ER, indicating that triphenylmethane‐induced changes in proliferative and transcriptional activities differ from conventional mechanisms of action triggered by other selective ER modulators.

A new family of densely functionalized fused-benzoquinones as potent human protein kinase CK2 inhibitors

A new series of 2-amino-4-phenyl-6-hydroxy-7-alkyl-pyranobenzoquinones was synthesized as ATP-competitive CK2 inhibitors. They were readily synthesized through a three-component Knoevenagel condensation-Michael addition-heterocyclization reaction from aldehydes, malononitrile, and 3-alkyl-2,5-dihydroxybenzoquinones. Some of the synthesized compounds presented interesting inhibitory activity with IC50 values in the submicromolar range. A structure-activity relationship study was carried out and the mode of binding was analysed by docking studies and supported by ATP competition assays.

Metal complexes of natural product like-compounds with antitumoral activity

Cancer continues to be one of the major causes of death worldwide. Despite many advances in the understanding of this complex disease, new approaches are needed to improve the efficacy of current therapeutic treatments against aggressive tumors. Natural products are one of the most consistently successful sources of drug leads. In recent decades, research activity into the clinical potential of this class of compounds in cancer has increased. Furthermore, a highly promising field is the use of metals and their complexes in the design and development of metal-based drugs for the treatment of cancer. Metal complexes offer unique opportunities due to their ability to alter pharmacology, improving the efficacy and/or reducing the negative side effects of drug molecules. In addition, transition metals as copper, iron, and manganese, among others, can interact with active sites of enzymes, playing important roles in multiple biological processes. Thus, these complexes not only possess higher activities but also reach their targets more efficiently. This review article highlights recent advances on the emerging and expanding field of metal-based drugs. The emphasis is on new therapeutic strategies consisting of metal complexes with natural product like-compounds as a starting point for the rational design of new antitumor agents.

Synthesis and antibacterial activity of new symmetric polyoxygenated dibenzofurans

A series of symmetric polyoxygenated dibenzofurans with 2-methylbutyril moieties at C-4 and C-6 were obtained from commercial phloroglucinol through a sequence of reactions that include monoacylation, iodination, Suzuki-Miyaura coupling, oxidative dimerization and cyclization. Some of the compounds obtained were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates. The dibenzofuran 28 with propyl chains at C-2 and C-8 exhibited the best antibacterial activity with values comparable to those of the natural dibenzofuran achyrofuran. From the obtained results some structure-activity relationships were outlined.