1,720,972 research outputs found
Natural products from higher plants and marine organisms as sources of new anticancer agents: synthesis and biological evaluation
Full text linkAbstract part A: The dysregulation of the Hedgehog (Hh) signaling pathway plays a pivotal role in the generation and cell-manteinance of many human cancers. Gli transcription factors, the final effectors of the pathway, represent the most promising target for the development of new drugs targeting the Hh pathway in tumors. In a previous work, a natural isoflavone, glabrescione B (GlaB) (I), was identified as the first small molecule binding Gli1. It is able to inhibit the transcriptional activity of Gli1, by interfering with its interaction with DNA. In order to perform further studies on the mechanism of action of GlaB (I) we developed a total synthesis, while NMR studies demonstrated the interaction of GlaB with Gli1
Biological studies have demonstrated its ability to interfere with the activity of Gli1 by inhibiting the growth of Gli-dependent-Hh-dependent tumor cells such as medulloblastoma (MB) and basal cell carcinoma (BCC) both in vitro and in allograft mouse models.
In addition, our new synthetic route, which encompasses just three steps with an overall yield of 15%, provided an efficient synthetic means to enable the investigation of the role of GlaB ring-B in the interaction Gli1-GlaB. In fact, our synthetic strategy allowed the preparation of several GlaB derivativesin order to elucidate the structure-activity relationships (SARs) and to clarify the molecular mechanism underlying its Hedgehog signalling modulation.Abstract part B: The second part of this PhD thesis describes the work I have carried out during my research stay abroad at Swiss Federal Institute of Technology (ETH) in Zürich (Switzerland) in Prof. Dr. Karl-Heinz Altmann's laboratory. Marine natural products show higher incidence of bioactivity compared to terrestrial natural products. This is due to a high degree of chemical novelty and their high dilution in ocean water. (+)-Dactylolide (I) was isolated by Riccio and co-workers from a sponge of the genus Dactylospongia, collected off the coast of Vanuatu islands, in the South Pacific Ocean. The absolute and the relative configuration at C19 of the compound remained unassigned. The assignment of the relative and absolute configuration of (+)-dactylolide (I) is based on its first total synthesis by Smith and co-workers. As had been described for the natural product, synthetic dactylolide has been found to be dextrorotatory, but the magnitude of the specific rotation reported for the natural product and synthetic I were significantly different from each other. In addition, the discrepancies between the 13C-NMR spectra of synthetic and natural (+)-dactylolide (if ever so slight), also leave open the possibility that the configuration of C19 in natural (+)-dactylolide is R and not S (i. e. natural dactylolide could have the structure II instead of I). In order to demonstrate that, a total synthesis of both compounds was established.
(+)-Dactylolide (I) is related to (-)-zampanolide (III), another marine macrolide. The latter shows low nanomolar cytotoxicity against both drug-sensitive and multi-drug resistant cancer cell lines, and induces microtubule bundle formation. While (-)-zampanolide (III) is a nM inhibitor of cancer cell growth in vitro, not many data about the activity of (+)-dactylolide (I) have been published. On the other hand, the biological activity of synthetic (-)-dactylolide (ent-I) is well known. This compound exhibits sub-μM IC50 values against a multitude of cancer cell lines, although (–)-zampanolide (III) is still 100- to 300-fold more potent. At the same time, not even synthetic (+)-zampanolide (ent-III) has ever been tested and the importance of the configuration of the macrocycle for the potency of dextrorotatory compounds remains unclear. Our goal was to synthesize (+)-dactylolide (I) and (+)-zampanolide (ent-III), in order to investigate how the macrocycle configuration would affect the biological activity of the compounds
One hundred faces of cyclopamine
No full textThe natural steroidal alkaloid cyclopamine has been identified as the first inhibitor of the Hedgehog (Hh) signaling pathway, which is implicated in embryonic development and tumorigenesis, as well as is hyperactivated in cancer stem cells (CSCs). The list of Hh-dependent tumors is steadily growing, and it has been estimated that about 25% of all cancer deaths show signs of aberrant Hh pathway activation. Notably, cyclopamine has been found to exert anticancer activity against several types of human cancer and to inhibit CSCs proliferation, thus highlighting the druggability of the Hh pathway and paving new opportunities in anticancer drug discovery. The aim of the present work is to review the main synthetic strategies to cyclopamine and its derivatives, with particular emphasis on the challenging chemical modifications aimed at improving the biological activity of the molecule
The plant-derived triterpenoid tingenin B is a potent anticancer agent due to its cytotoxic activity on cancer stem cells of breast cancer in vitro
No full textDespite the rapid advances in chemotherapy regimens, the outcome of patients with breast cancer is not satisfactory. One of the reasons of this dissatisfaction is that subsets of cells in tumors which referred as cancer stem cells (CSCs) show and/or gain resistance to therapies. Thus, compounds that target CSCs are urgently needed. Since some are already used in the clinic, natural products have great potential for further development as anti cancer drugs. The aim of this study is to investigate the cytotoxic activity of tingenin b (or 22β-hydroxytingenone) which is a quinone-methide triterpenoid structurally related to tingenone, against breast CSCs (stem-cell enriched population from MCF-7 cell line, MCF-7s). It has been found that tingenin b was cytotoxic against MCF-7s (IC50 value for 48 h was found to be 2.38 μM) by inducing apoptosis. It was evident by Annexin V staining positivity, decreased mitochondrial membrane potential and Bcl-2 dephosphorylation with a concomitant increase in Bax protein expression. In addition, endoplasmic reticulum stress was also found to be involved in tingenin b-induced cell death. In conclusion, the results warrant further studies aimed at elucidating and corroborating its possible use in the treatment of breast cancer
The pictet-spengler reaction still on stage
No full textToday, in spite of being older than a century (born in 1911), the Pictet-Spengler two component reaction (PS-2CR) is still one of the most popular reactions, not only for the synthesis of tetrahydroisoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), or more complex structures containing these two privileged moieties, but also for the construction of novel scaffolds, available for structure-activity relationship (SAR) studies and/or for combinatorial libraries targeted at drug discovery. The prominence of the P-S cyclization is brought about by the inheritance from analogous enzyme-catalyzed reactions of the biogenetic pathways of natural products, mainly indole alkaloids, with a broad range of biological activities. This knowledge has been the starting point for the biomimetic synthesis or the bio-engineering production of pharmacologically important drugs. The long-lasting life of the P-S reaction depends on the discovery of its multiple facets, the modifications of its parameters and components, as well as the continuous renovation of solutions for the challenging stereochemical outcome of the transformation. This paper deals with an updated visit to the P-S reaction aiming to find the threads of the story without forgetting the numerous facets of the prism. It is organized as a theater piece, with a prologue and the main scene (namely, Act 1) where the readers can follow the parade of the two above-mentioned very recurring motifs (namely, THIQ and THBC) by moving from one step to another (a cyclization, an intramolecular attack, a stereoselective passage) to find the way out of the labyrinth of the P-S reaction
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Occurrence of enantioselectivity in nature: The case of (S)-norcoclaurine
No full textThis review article is aimed at providing a monographic overview on (S)-norcoclaurine (NC) alkaloid from three diverse points of view, collected all together for the first time: 1) the synthetic one, where the compound is seen as a target chiral molecule to be obtained in the highest optical purity and as a starting point for the development of biocatalytic asymmetric syntheses of tetrahydroisoquinoline alkaloids; 2) the chromatographic one, which addresses the HPLC separation of the two NC enantiomers; and 3) the biochemical one, for which a thorough understanding of the topology and mechanism of action of norcoclaurine synthase (NCS) enzyme is still a matter of debate. Special emphasis on the most recent studies in the field is given by discussing the results
published by the main research groups who are working on NC and NCS
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
