Synthesis of new bengamide analogues and encapsulation into thermo-responsive magnetic nanoparticles

The development and identification of new antitumoral drugs has become a research area of great interest and maximum priority. Firstly, to overcome the secondary effects frequently shown by current antitumorals and, secondly, to prevent the appearance of tumours resistance to these agents. Marine sponges corresponding to the Jaspidae family have proved to be a prolific source of bioactive natural products. Among these, the bengamides have showed an important biological profile, including antitumor, antibiotic and anthelmintic properties. We describe here a study directed towards the total synthesis of bengamides including their encapsulation into temperature-sensitive microgels having magnetic Fe3O4 cores. Magnetic nanoparticles were prepared by the coprecipitation method and show an acrylic acid surface functionalization. We chose poly(N-isopropylacrylamide) (PNIPAM) as polymeric material, which was grown by a free radical polymerization process.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Synthesis of New Analogues of the Bengamides: Peptidyl Bengamides and Molecular Probes

Isolated from sponges of the Jaspidae family, first members where discovered in 1986. The bengamides represent an interesting and unprecedented family of natural products that displayed striking antitumor activities [1]. The recognition of these natural products as antiangiogenic compounds, in virtue to their inhibition of methionine aminopeptidases, prompted intense research activities in the chemical and biological fields. In fact, the total synthesis of the natural products, together with an extensive variety of analogues, has been reported in the literature [2]. Particularly, we have recently developed a new synthetic methodology which allowed rapid and efficient access to the natural bengamide E (1), together with a wide library of analogues of which the cyclopentyl analogue 2 was identified as a more potent antitumor compound with respect to its natural congener [3]. As continuation of these synthetic efforts, with the objective of identifying new potent and promising analogues, we wish to report our recent synthetic studies directed to the synthesis of new bengamide analogues, featured by the replacement of the caprolactam fragment by a peptidyl residue (compounds type 3). On the other hand, in order to gain insight into the mechanism of the biological action of the bengamides, we describe the preparation of the N-alkyl derivatives 4 and 5, which represent interesting molecules that could be employed as suitable molecular probes.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.Supported by grants RTI2018-098296-BI00 (Ministerio de Ciencia e Innovación), PI19/01478 from Instituto de Salud Carlos III (ISCIII) (FEDER), P20_00540 (Andalusian Government and FEDER), K99GM138758 and R35GM136286 (National Institute of General Medical Sciences of the National Institutes of Health), A-CTS-666-UGR20 (University of Granada) (FEDER), CTS-107 (Andalusian Government) and 2021-GRIN-30998 (University of Castilla-La Mancha). Partial funding for open access charge: Universidad de Málag

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry

Bengamide Analogues Show A Potent Antitumor Activity against Colon Cancer Cells: A Preliminary Study.

The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC

Magnetically active pNIPAM nanosystems as temperature-sensitive biocompatible structures for controlled drug delivery

Here, temperature-sensitive hybrid poly(N-isopropylacrylamide) (pNIPAM) nanosystems with magnetic response are synthesised and investigated for controlled release of 5-fluorouracil (5FU) and oxaliplatin (OXA). Initially, magnetic nanoparticles (@Fe3O4) are synthesised by co-precipitation approach and functionalised with acrylic acid (AA), 3-butenoic acid (3BA) or allylamine (AL) as comonomers. The thermoresponsive polymer is grown by free radical polymerisation using N-isopropylacrylamide (NIPAM) as monomer, N,N’-methylenbisacrylamide (BIS) as cross-linker, and 2,2’-azobis(2-methylpropionamidene) (V50) as initiator. We evaluate particle morphology by transmission electron microscopy (TEM) and particle size and surface charge by dynamic light scattering (DLS) and Z-potential (ZP) measurements. These magnetically active pNIPAM@ nanoformulations are loaded with 5-fluorouracil (5FU) and oxaliplatin (OXA) to determine loading efficiency, drug content and release as well as the cytotoxicity against T-84 colon cancer cells. Our results show high biocompatibility of pNIPAM nanoformulations using human blood cells and cultured cells. Interestingly, the pNIPAM@Fe3O4-3BA þ 5FU nanoformulation significantly reduces the growth of T-84 cells (57% relative inhibition of proliferation). Indeed, pNIPAM-co-AL@Fe3O4-AA nanosystems produce a slight migration of HCT15 cells in suspension in the presence of an external magnetic field. Therefore, the obtained hybrid nanoparticles can be applied as a promising biocompatible nanoplatform for the delivery of 5FU and OXA in the improvement of colon cancer treatments.MINECO CTQ16-76311Atraccion de Talento fellowship from the Comunidad de Madrid 2018-T1/IND-10736Junta de Andalucía PI-0476-2016 PI-0102-2017Instituto de Salud Carlos III PI19/01478Ministerio de Educación, Ciencia y Deporte y Competitividad (Spain) FPU16_0171

Magnetically active pNIPAM nanosystems as temperature-sensitive biocompatible structures for controlled drug delivery.

Here, temperature-sensitive hybrid poly(N-isopropylacrylamide) (pNIPAM) nanosystems with magnetic response are synthesised and investigated for controlled release of 5-fluorouracil (5FU) and oxaliplatin (OXA). Initially, magnetic nanoparticles (@Fe3O4) are synthesised by co-precipitation approach and functionalised with acrylic acid (AA), 3-butenoic acid (3BA) or allylamine (AL) as comonomers. The thermo-responsive polymer is grown by free radical polymerisation using N-isopropylacrylamide (NIPAM) as monomer, N,N'-methylenbisacrylamide (BIS) as cross-linker, and 2,2'-azobis(2-methylpropionamidene) (V50) as initiator. We evaluate particle morphology by transmission electron microscopy (TEM) and particle size and surface charge by dynamic light scattering (DLS) and Z-potential (ZP) measurements. These magnetically active pNIPAM@ nanoformulations are loaded with 5-fluorouracil (5FU) and oxaliplatin (OXA) to determine loading efficiency, drug content and release as well as the cytotoxicity against T-84 colon cancer cells. Our results show high biocompatibility of pNIPAM nanoformulations using human blood cells and cultured cells. Interestingly, the pNIPAM@Fe3O4-3BA + 5FU nanoformulation significantly reduces the growth of T-84 cells (57% relative inhibition of proliferation). Indeed, pNIPAM-co-AL@Fe3O4-AA nanosystems produce a slight migration of HCT15 cells in suspension in the presence of an external magnetic field. Therefore, the obtained hybrid nanoparticles can be applied as a promising biocompatible nanoplatform for the delivery of 5FU and OXA in the improvement of colon cancer treatments

Inhibition of Endothelial Inflammatory Response by HT-C6, a Hydroxytyrosol Alkyl Ether Derivative

Hydroxytyrosol (HT) is a bioactive phenolic compound naturally present in olives and extra virgin olive oil (EVOO) which is described as an antioxidant, antitumoral and antiangiogenic molecule. Previous studies of semi-synthetic HT-derivatives presented the hydroxytyrosyl alkyl ether HT-C6 as one of the most potent derivatives studied in the context of antioxidant, anti-platelet and antiangiogenic assays, but its direct effect on inflammation was not reported. In this work, we use RT-qPCR measure of gene expression, protein analysis by Western-blot and immunofluorescence techniques, adhesion and migration functional assays and single-cell monitoring of reactive oxygen species (ROS) in order to explore in vitro the ability of HT-C6 to interfere in the inflammatory response of endothelial cells (ECs). Our results showed that HT-C6 strongly reduces the TNF-α-induced expression of vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule 1 (ICAM1), E-selectin (SELE), C-C motif chemokine ligand 2 and 5 (CCL2 and CCL5) in HUVECs, impairing the chemotactic and adhesion potential of these cells towards THP-1 monocytes in vitro. In this work, we define a mechanism of action underlying the anti-inflammatory effect of HT-C6, which involves the abrogation of nuclear factor kappa B (NF-κB) pathway activation in ECs. These results, together with the ability of HT-C6 to reduce ROS formation in ECs, point to this compound as a promising HT-derivative to be tested in the treatment of atherosclerosis