Publications by authors named "Laura Scarone"

5 Publications

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Novel distamycin analogues that block the cell cycle of African trypanosomes with high selectivity and potency.

Eur J Med Chem 2020 Mar 8;189:112043. Epub 2020 Jan 8.

Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay. Electronic address:

Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.
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http://dx.doi.org/10.1016/j.ejmech.2020.112043DOI Listing
March 2020

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing -Methyl Amino Acids as Antiplasmodial Agents.

ACS Med Chem Lett 2019 Jan 26;10(1):137-141. Epub 2018 Dec 26.

Laboratorio de Química Farmacéutica (DQO), Facultad de Química, Universidad de la República, Gral. Flores 2124, Montevideo, CP 11800, Uruguay.

Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing -methyl amino acids with activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, evaluation, and mice pharmacokinetics are described.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331169PMC
January 2019

In vitro activity and mode of action of distamycin analogues against African trypanosomes.

Eur J Med Chem 2017 Jan 2;126:776-788. Epub 2016 Dec 2.

Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address:

Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC 310 nM and selectivity index 16) than the control drug nifurtimox (EC 15 μM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.002DOI Listing
January 2017

Macrocycles as potential therapeutic agents in neglected diseases.

Future Med Chem 2015 4;7(3):355-82. Epub 2015 Feb 4.

Cátedra de Química Farmacéutica, (DQO), Facultad de Química, Universidad de la República, Gral. Flores 2124, Montevideo, CP 11800, Uruguay.

Macrocycles possess desirable properties that make them promising candidates for the discovery of novel drugs. They present structural features to favor bioactive conformations, selectivity to the receptors, cell permeability and metabolic stability. More effective and nontoxic drugs to cure human African trypanosomiasis, Leishmaniasis and Chagas disease are needed, especially because resistance has been detected. Therefore, major efforts should be made for investigation in new bioactive compounds exhibiting different mechanisms of action. Macrocycles might fulfill the expectations for the development of new drugs to treat those diseases. In the current review, we focus on macrocycles exhibiting biological activities as antitrypanosomal and/or antileishmanial. The isolation, synthetic and biological studies of this class of compounds published from 2005 to 2014 are summarized.
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http://dx.doi.org/10.4155/fmc.14.133DOI Listing
December 2015

Synthesis of a Microcystis aeruginosa predicted metabolite with antimalarial activity.

Bioorg Med Chem Lett 2012 Aug 16;22(15):4994-7. Epub 2012 Jun 16.

Cátedra de Química Farmacéutica, DQO, Facultad de Química, UDELAR, Montevideo CP 11800, Uruguay.

The synthesis of a Microcystis aeruginosa predicted metabolite analog of aerucyclamide B was performed. This hexacyclopeptide was obtained from three heterocyclic building blocks by a convergent macrocycle-assembly methodology. The compound exhibited good in vitro antiplasmodial activity (IC(50): 0.18 μM, K1, cholorquine resistant strain).
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http://dx.doi.org/10.1016/j.bmcl.2012.06.028DOI Listing
August 2012
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