Synthesis of the Macrocylic Core of the Solomonamides, a New Class of Cyclopeptides of Marine Origin

Se describe estudios sintéticos dirigidos hacia la síntesis total de solomonamides, una nueva clase de ciclopéptidos de origen marino que presentan interesantes propiedades biológicas. La aproximación sintética se basó en la metátesis de cierre de anillo como vía para formar el sistema macrocíclico de forma rápida y eficaz.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Total synthesis of depudecin and analogues via an olefin cross-metathesis based strategy

(-)-Depudecin (1), isolated from the culture broths of the fungus Alternaria brassicicola [1], has been identified as a selective inhibitor of histone deacetylases (HDAC) with an IC50 in the low μM range. In contrast to representative HDAC inhibitors, depudecin represents a unique inhibitor of these enzymes by virtue of its molecular structure, featuring the presence of two oxirane rings separated by a trans double bond. Originally discovered as part of a biological screen directed towards the identification of antitumour agents with detransforming activity [2], depudecin was identified as a bioactive metabolite capable of reverting the transformed morphology of tumor cells. Depudecin induced cell cycle arrest and cellular differentiation [3], and also exhibited anti-angiogenesis activity [4]. Prompted by its striking biological properties and enticing structure, we decided to initiate a research program directed towards the synthesis of natural depudecin which has recently culminated with a linear total synthesis [5]. In order to develop an improved access to natural depudecin and analogues for further biological screenings, we explored a synthetic alternative as a shorter and more convergent approach. In this communication we report a new total synthesis of the natural product (-)-depudecin. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin. This strategy was applied to the preparation of the 10-epi and (+)-depudecin, which represent interesting stereoisomeric analogues for SAR studies.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

Synthesis and biological activity of a new class of antitumor cyclopeptides based on the solomonamides

Solomonamides A (1) and B (2) are novel natural products recently isolated from the marine sponge Theonella swinhoei [1]. Preliminary structural studies revealed an unprecedented cyclic peptide type structure. Interestingly, solomonamide A exhibits anti-inflammatory activity, showing potent reduction (60%) of inflammation at a very low concentration of 100 µg/kg in animal models. However, the scarcity of these compounds from their natural sources has been a drawback for further pharmacological assays. In fact, the anti-inflammatory activity of solomonamide B was not evaluated due to the limited amounts. This difficulty to access large amounts of these compounds makes quite difficult to gain insight into their biological profiles and mechanism of action and justifies the chemical synthesis of this new class of cyclic peptides. As a consequence, the solomonamides have been the subject of several synthetic efforts [2] notably by the Reddy group who has recently reported the first total synthesis of solomonamide B based on a intramolecular Heck reaction, which led to a revision of the initially proposed structure for 2 [3].Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Antitumor and antiangiogenic potential of solomonamide synthesis intermediates

Es comunicación (formato panel) a congreso internacionalIn this work we developed a new synthetic strategy towards the solomonamides. a novel class of cyclopeptides of marine origin. The described synthetic approach utilized an olefin metathesis reaction to form the [15]-membered ring contained in these natural products. During the synthetic process, a diverse set of analogues was generated and we evaluated their potential antitumor activity in vitro. For this purpose we performed in vitro proliferation assays, determining the IC50 values of the compounds in a panel of tumor cell lines. In addition, we evaluated the possible antiangiogenic effects of these solomonamide analogues by using in vitro endothelial cell differentiation assays. Our results showed that the potential antitumor and antiangiogenic activity of the studied analogues depended on their chemical structure, suggesting that the presence of specific functional groups could be responsible of their biological activity. Further studies are needed to understand the basis of the observed activities in endothelial and tumor cells.Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). This communicaction has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Exploring the ring-closing metathesis for the construction of the solomonamide macrocyclic core: identification of bioactive precursors

New synthetic strategies directed toward the novel cyclopeptides solomonamides have been explored utilizing an olefin metathesis as the key reaction. In the various strategies investigated, we worked on minimally oxidized systems, and the olefin metathesis reaction demonstrated efficiency and validity for the construction of the macrocyclic core. The described synthetic strategies toward the solomonamides are well suited for the subsequent access to the natural products and represent flexible and diversityoriented routes that allow for the generation of a variety of analogues via oxidative transformations. In addition, preliminary biological evaluations of the generated solomonamide precursors revealed antitumor activity against various tumor cell lines.This work was financially supported by the Ministerio de Economía y Competitividad (MINECO) (ref BIO2014-56092-R, CTQ2014-60223-R and CTQ2016-76311-R) and Junta de Andalucía and “Fondo Europeo de Desarrollo Regional-FEDER” (P12 CTS-1507). I.C.-S. thanks Ministerio de Educación, Cultura y Deporte for a predoctoral fellowship (FPU programme)

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

Synthesis and Biological Evaluation of Depudecin Analogues

(-)-Depudecin (1) (Figure 1), isolated from the culture broths of the fungus Alternaria brassicicola,1 and later, from the weed pathogen Nimbya scirpicola,2 has been identified as a selective inhibitor of histone deacetylases (HDAC) with an IC50 in the low M range.3 In contrast to representative HDAC inhibitors, depudecin represents a unique inhibitor of these enzymes by virtue of its molecular structure, featuring the presence of two oxirane rings separated by a trans double bond. Originally discovered as part of a biological screening directed towards the identification of antitumour agents with detransforming activity,4 depudecin was identified as a bioactive metabolite capable of reverting the transformed morphology of tumor cells. This biological activity elicited a great biomedical and biological interest by virtue of its potential as an antitumor agent as well as for further understanding the biological roles of HDACs. Depudecin induced not only morphological changes but also cell cycle arrest and cellular differentiation,5 and also exhibited remarkable anti-angiogenesis activity.6 Prompted by its striking biological properties and enticing structure, we decided to initiate a research program directed towards the synthesis of natural depudecin. Our synthetic plan has recently culminated with linear and convergent total syntheses.7Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

First M87 Event Horizon Telescope Results. VI. The Shadow and Mass of the Central Black Hole

We present measurements of the properties of the central radio source in M87 using Event Horizon Telescope data obtained during the 2017 campaign. We develop and fit geometric crescent models (asymmetric rings with interior brightness depressions) using two independent sampling algorithms that consider distinct representations of the visibility data. We show that the crescent family of models is statistically preferred over other comparably complex geometric models that we explore. We calibrate the geometric model parameters using general relativistic magnetohydrodynamic (GRMHD) models of the emission region and estimate physical properties of the source. We further fit images generated from GRMHD models directly to the data. We compare the derived emission region and black hole parameters from these analyses with those recovered from reconstructed images. There is a remarkable consistency among all methods and data sets. We find that >50% of the total flux at arcsecond scales comes from near the horizon, and that the emission is dramatically suppressed interior to this region by a factor >10, providing direct evidence of the predicted shadow of a black hole. Across all methods, we measure a crescent diameter of 42 +/- 3 mu as and constrain its fractional width to b

First M87 Event Horizon Telescope Results. IV. Imaging the Central Supermassive Black Hole

We present the first Event Horizon Telescope (EHT) images of M87, using observations from April 2017 at 1.3 mm wavelength. These images show a prominent ring with a diameter of similar to 40 mu as, consistent with the size and shape of the lensed photon orbit encircling the "shadow" of a supermassive black hole. The ring is persistent across four observing nights and shows enhanced brightness in the south. To assess the reliability of these results, we implemented a two-stage imaging procedure. In the first stage, four teams, each blind to the others' work, produced images of M87 using both an established method (CLEAN) and a newer technique (regularized maximum likelihood). This stage allowed us to avoid shared human bias and to assess common features among independent reconstructions. In the second stage, we reconstructed synthetic data from a large survey of imaging parameters and then compared the results with the corresponding ground truth images. This stage allowed us to select parameters objectively to use when reconstructing images of M87. Across all tests in both stages, the ring diameter and asymmetry remained stable, insensitive to the choice of imaging technique. We describe the EHT imaging procedures, the primary image features in M87, and the dependence of these features on imaging assumptions