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

Quantifying the impact of financial development on economic development

How important is financial development for economic development? A costly state verification model of financial intermediation is presented to address this question. The model is calibrated to match facts about the U.S. economy, such as intermediation spreads and the firm-size distribution for the years 1974 and 2004. It is then used to study the international data, using cross-country interest-rate spreads and per-capita GDP. The analysis suggests a country like Uganda could increase its output by 140 to 180 percent if it could adopt the world?s best practice in the financial sector. Still, this amounts to only 34 to 40 percent of the gap between Uganda?s potential and actual output.Economic development ; Intermediation (Finance)

Financing development: the role of information costs

To address how technological progress in financial intermediation affects the economy, a costly state verification framework is embedded into the standard growth model. The framework has two novel ingredients. First, firms differ in the risk/return combinations that they offer. Second, the efficacy of monitoring depends upon the amount of resources invested in the activity. A financial theory of firm size results. Undeserving firms are over financed, deserving ones under funded. Technological advance in intermediation leads to more capital accumulation and a redirection of funds away from unproductive firms toward productive ones. With continued progress, the economy approaches its first-best equilibrium.Economic development ; Intermediation (Finance)

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

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)

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

Di-μ-chlorido-bis­{[N,N′-dicyclo­hexyl-N′′,N′′-bis­(trimethyl­sil­yl)guanidinato-κ2 N,N′](tetra­hydro­furan-κO)magnesium(II)}

The dinuclear title complex, [Mg2(C19H40N3Si2)2Cl2(C4H8O)2], lies on a center of inversion. The Mg2+ ions are bonded to a chelating N,N′-bonded guanidinate anion, a tetra­hydro­furan mol­ecule and two bridging chloride anions. The geometry of the resulting five-coordinated Mg2+ ion is a very distorted square-based pyramid with the O atom in the apical position