Synthesis, biological and computational evaluation of novel cyanomethyl vinyl ether derivatives.

This work explores the biological evaluation of novel cyanomethyl vinyl ether derivatives as antiproliferative agents. Tubulin, crucial to microtubule structure and function, is a target for cancer therapies. cytotoxicity assessments revealed significant activity in SKOV3 ovarian carcinoma cells and A549 lung carcinoma cells.

Antileishmanial Effect of 1,5- and 1,8-Substituted Fused Naphthyridines.

In the absence of a vaccine, there is a need to find new drugs for the treatment of neglected tropical diseases, such as leishmaniasis, that can overcome the many drawbacks of those currently used. These disadvantages include cost, the need to maintain a cold chain, the route of administration, the associated adverse effects and the generation of resistance. In this work we have evaluated the antileishmanial effect of 1,5- and 1,8-substituted fused naphthyridines through in vitro and ex vivo assays, using genetically modified axenic and intramacrophagic amastigotes.

Aza-Povarov Reaction. A Method for the Synthesis of Fused Tetracyclic Chromeno[4,3-]pyrido[1,2-]pyrimidines.

A cornerstone in drug discovery is the development of strategies to provide privileged small molecules with specific structural and stereochemical complexity, allowing access to new potential therapeutic entities. In this work, a new strategy based on the [4 + 2] Povarov reaction involving 1,3-diazadiene was developed. This approach is applied for a straightforward procedure in the preparation of chromeno[4,3-]pyrido[1,2-]pyrimidine derivatives, with accessible substrates, 2-aminopyridine and unsaturated aldehydes, and excellent atom economy to obtain four fused ring heterocycles, in a regio- and diastereoselective way.

The Intramolecular Povarov Tool in the Construction of Fused Nitrogen-Containing Heterocycles.

Nitrogen heterocycles are part of the structure of natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs. For this reason, heterocyclic compounds are one of today's most desirable synthetic targets and the Povarov reaction is a powerful synthetic tool for the construction of highly functionalized heterocyclic systems. This process involves an aromatic amine, a carbonyl compound, and an olefin or acetylene to give rise to the formation of a nitrogen-containing heterocycle.

Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds.

With the increasing need for effective compounds against cancer or pathogen-borne diseases, the development of new tools to investigate the enzymatic activity of biomarkers is necessary. Among these biomarkers are DNA topoisomerases, which are key enzymes that modify DNA and regulate DNA topology during cellular processes. Over the years, libraries of natural and synthetic small-molecule compounds have been extensively investigated as potential anti-cancer, anti-bacterial, or anti-parasitic drugs targeting topoisomerases.

Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers.

Background: Several studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown.

Patients And Methods: To ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN.

Efficient AntiMycolata Agents by Increasing the Lipophilicity of Known Antibiotics through Multicomponent Reactions.

New antibiotic agents were prepared using Povarov and Ugi multicomponent reactions upon the known drugs sulfadoxine and dapsone. The prepared derivatives, with increased lipophilicity, showed improved efficiency against Mycolata bacteria. Microbiological guidance for medicinal chemistry is a powerful tool to design new and effective antimicrobials.

Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group.

We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure-activity profile is presented.

Hydrogen sulphide-triggered theranostic prodrugs based on the dynamic chemistry of tetrazines.

Dynamic nucleophilic aromatic substitution of tetrazines (STz) has been employed to build theranostic prodrugs that are activated by hydrogen sulfide. HS is typically found in high concentrations in some kinds of cancer cells and it is able to trigger the disassembly of tetrazine prodrugs. In such a way, a dual release of drugs and/or fluorescent compounds can be selectively triggered.

The design and discovery of topoisomerase I inhibitors as anticancer therapies.

Introduction: Cancer has been identified as one of the leading causes of death worldwide. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds with antiproliferative effect and behaving as topoisomerase I inhibitors has become an active field of research.

Synthesis of hybrid phosphorated indenoquinolines and biological evaluation as topoisomerase I inhibitors and antiproliferative agents.

This work describes the first synthesis of diethyl 6,6a,7,11b-tetrahydro-5H-indeno[2,1-c]quinolinylphosphonates 5, diethyl 7H-indeno[2,1-c]quinolinylphosphonates 6 and diethyl 7-oxo-7H-indeno[2,1-c]quinolinylphosphonates 7, which were prepared in good to high overall yields. The synthetic route involves a multicomponent reaction of 2-phosphonateaniline, aldehydes and indene as olefin and allows the selective generation of three stereogenic centres in a short, efficient and reliable manner. The selective dehydrogenation of 1,2,3,4-tetrahydroindenoquinolines leads to the formation of corresponding indenoquinolines, and subsequent oxidation of methylene group of the indenoquinolines allows the access to indenoquinolinones.

Naphthyridine Derivatives Induce Programmed Cell Death in .

Primary amoebic encephalitis (PAM) caused by the opportunistic pathogen is characterized as a rapid and lethal infection of the brain which ends in the death of the patient in more than 90% of the reported cases. This amoeba thrives in warm water bodies and causes infection after individuals perform risky activities such as splashing or diving, mostly in non-treated water bodies such as lakes and ponds. Moreover, the infection progresses very fast and no fully effective molecules have currently been found to treat PAM.

Simple and Fast DNA Based Sensor System for Screening of Small-Molecule Compounds Targeting Eukaryotic Topoisomerase 1.

: Eukaryotic topoisomerase 1 is a potential target of anti-parasitic and anti-cancer drugs. Parasites require topoisomerase 1 activity for survival and, consequently, compounds that inhibit topoisomerase 1 activity may be of interest. All effective topoisomerase 1 drugs with anti-cancer activity act by inhibiting the ligation reaction of the enzyme.

Hybrid Quinolinyl Phosphonates as Heterocyclic Carboxylate Isosteres: Synthesis and Biological Evaluation against Topoisomerase 1B (TOP1B).

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation.

A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors.

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1.

Fused chromeno and quinolino[1,8]naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents.

The synthesis of 1,8-naphthyridine derivatives fused with other heterocycles, such as chromenes and quinolines, as well as their behaviour as topoisomerase I inhibitors is studied. The preparation is carried out through a direct and simple process as an intramolecular [4 + 2] cycloaddition reaction between functionalized aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, and olefins. In particular, while no clear inhibitory activity is observed for chromeno[4,3-b][1,8]naphthyridine fused heterocycles, a very different result is observed for quinolino[4,3-b][1,8]naphthyridine derivatives.

A patent review of topoisomerase I inhibitors (2016-present).

Introduction: Topoisomerases are important targets for therapeutic improvement in the treatment of some diseases, including cancer. Inhibitors and poisons of topoisomerase I can limit the activity of this enzyme in its enzymatic cycle. This fact implies an anticancer effect of these drugs, since most cancer cells are characterized by both a higher activity of topoisomerase I and a higher replication rate compared to non-cancerous cells.

Familial hypercholesterolemia: A single-nucleotide variant (SNV) in mosaic at the low density lipoprotein receptor (LDLR).

Background And Aims: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes.

Fused 1,5-Naphthyridines: Synthetic Tools and Applications.

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold.

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines.

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes.

Novel phosphine sulphide gold(i) complexes: topoisomerase I inhibitors and antiproliferative agents.

This work describes the synthesis of the gold(i) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(i) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(i)-complexed compounds against the cancer line A549 with IC values in the nanomolar range and IC values below 5 μM against the SKOV3 cell line.

Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives.

The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al.

New Challenges in Drug Discovery - July 8-11, 2019, Vitoria-Gasteiz, Spain.

The 2019 edition "New Challenges in Drug Discovery", one of the biennial meetings under the patronage of the SEQT and EFMC, was held at the Faculty of Pharmacy of the University of the Basque Country in Vitoria-Gasteiz from July 8 to 11, 2019. On this occasion, attendees from Spain as well as from five EU countries and three non-EU countries were spectators of many scientific highlights related with the main research areas for different diseases and with protein-protein interactions, analytical tools and methods in discovery and development of drugs and computer-assisted methods in medicinal chemistry. The interesting scientific program was also complemented by an entertaining social program: a gastronomic opening ceremony held at the Museum of Fine Arts of Alava, visits to the Medieval Old City of Gasteiz and a gala dinner in a typical restaurant nestled in a building from the XVth Century.

Straightforward synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents of hybrid Chromeno[4,3-b][1,5]Naphthyridines and Chromeno[4,3-b][1,5]Naphthyridin-6-ones.

This work describes the synthesis of hybrid tetrahydro-1,5-naphthyridine and 1,5-naphthyridine derivatives fused with heterocycles such as chromenes and chromen-2-ones or coumarins, which were synthesized in good to high general yields. The synthetic route involves an intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and aldehydes containing a double or triple carbon-carbon bond in orto position and allows the selective generation of three stereogenic centers in a short, efficient and reliable synthesis. The subsequent dehydrogenation of the fused tetrahydrochromeno[4,3-b][1,5]naphthyridines and/or tetrahydrochromeno[4,3-b][1,5]naphthyridin-6-ones leads to the formation of the corresponding tetracyclic chromeno[4,3-b][1,5]naphthyridine derivatives and/or chromeno[4,3-b][1,5]naphthyridin-6-ones in quantitative yields.