Alternative pathways for vitamin biosynthesis mediated by in vitro selected nucleic acids

The aim of this project is to select an RNAzyme by means of SELEX (Systemic Evolution of Ligands by Exponential Enrichment) that converts a synthetic precursor of an intermediate in the VitB1 (thiamin) biosynthesis into the thiamine precursor itself. In this way, the prethiamin precursor will lead to the biosynthesis of thiamin (in an appropriate auxothrophic strain), via a reaction that is not part of the natural thiamin biosynthesis pathway. This project will be the first example of an organism dependent on the activity of a synthetic (non-natural) nucleic acids enzyme and a major breakthrough in Synthetic Biology. It is also the first step towards rendering an organism dependent on a synthetic cofactor and ultimately reaching orthogonality in the level of metabolism.status: publishe

Vitamin-guanosine monophosphate conjugates for in vitro transcription priming

International audienceExpanding the catalytic repertoire of ribozymes to include vitamin synthesis requires efficient labelling of RNA with the substrate of interest, prior to in vitro selection. For this purpose, we rationally designed and synthesized six GMP-conjugates carrying a synthetic pre-thiamine or biotin precursor and investigated their transcription incorporation properties by T7 RNA polymerase

Vitamin-guanosine monophosphate conjugates for in vitro transcription priming.

Expanding the catalytic repertoire of ribozymes to include vitamin synthesis requires efficient labelling of RNA with the substrate of interest, prior to in vitro selection. For this purpose, we rationally designed and synthesized six GMP-conjugates carrying a synthetic pre-thiamine or biotin precursor and investigated their transcription incorporation properties by T7 RNA polymerase.status: publishe

N-substituted pyrrole-based scaffolds as potential anticancer and antiviral lead structures

Undoubtedly, efficient cancer treatment has been a significant challenge for the scientific community over the last decades. Despite tremendous progress made towards this direction, there are still efforts needed to discover new anticancer drugs. In this work, a series of N-substituted pyrrolebased scaffolds have been synthesized and evaluated for antiproliferative activity against a panel of cancer cell lines (L1210, CEM and HeLa). Furthermore, in order to discover new scaffolds as antiviral agents, all the examined compounds were evaluated for activity against different types of DNA and RNA viruses. The key feature of the above structures is the existence of an aromatic ring with at least one hydrogen-bonding donor and acceptor group. Results have shown noteworthy cytostatic activity for three of the synthesized compounds (1, 3 and 9). Especially, compound 1, containing a tropolone ring, proved to be the most promising scaffold (IC50:10-14 µM) for the development of novel potential anticancer agents. In addition, compound 1 has shown modest anti-HSV-1, -HSV2 activity in HEL cell cultures (EC50: 27-40 µM).status: publishe

Sustainable metal catalysis in C H activation

The omnipresence of C–H bonds in organic compounds renders them highly attractive targets for the installation of functional groups towards the construction of valuable molecular scaffolds. Consequently, C–H activation has extended beyond scientific curiosity and has evolved from being a concept of fundamental interest to constituting an important, modern tool of organic synthesis. The intensity of research efforts and accompanying discussion surrounding this topic has given rise to a plethora of innovative, cutting-edge advancements. These advancements demonstrate the vast potential of the C–H activation approach regarding the design of highly efficient and selective catalytic methodologies for the synthesis of fine chemicals, natural products, and advanced materials. However, the overall sustainable nature of this approach, emanating from some of its main attributes such as atom- and step-economy, is compromised by the frequent need of homogeneous catalysts based on rare, expensive, and even toxic noble transition metals. In order to address this issue and achieve truly sustainable catalytic C–H activation, significant research efforts have focused on the development of homogeneous catalytic systems based on more abundant, first row transition metals. In this respect, various catalytic protocols involving the use of highly abundant, inexpensive, readily available, and also biorelevant metals such as Mg, Ca, Mn, Fe, Cu, and Zn have been elegantly developed in recent years. Catalysts based on the aforementioned sustainable metals exhibit unique behavior in terms of reactivity/selectivity and their use does not only provide an alternative to noble metal catalysis, but also expands the scope of C–H activation. The present review provides a comprehensive examination of selected works that highlight the evolution and growing importance of this merge of two vibrant concepts in modern organic synthesis: sustainable metal catalysis and C–H activation. © 2017 Elsevier B.V

Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation

Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a trifluoroacetyl group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2 = 0.043−0.242 μΜ, Selectivity index = 190−858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex vivo and to exhibit substrate-specific inhibition

Pneumonia and Pleural Empyema due to a Mixed Lactobacillus spp. Infection as a Possible Early Esophageal Carcinoma Signature

Lactobacilli are human commensals found in the gastrointestinal and genitourinary tract. Although generally conceived as non-pathogenic microorganisms, the existence of several reports implicating them in certain severe pathological entities renders this species as opportunistic pathogens. The case of a 58-year-old woman with mixed Lactobacillus infection is described. The patient was admitted in an outpatient clinic with community acquired pneumonia, and on the third day of hospitalization she presented rapid pneumonia deterioration. Subsequent imaging techniques revealed increased pleural empyema in alignment with the general deterioration of her clinical condition. Pleural fluid culture revealed the presence of Lactobacillus delbrueckii and Lactobacillus gasseri and the infection was successfully treated with clindamycin. Five months after hospital discharge and an overall good condition, the patient developed signs of dysphagia and upon re-admission an inoperable esophageal carcinoma was diagnosed. The patient succumbed to the cancer 11 months later. Herein, we report for the first time a mixed respiratory infection due to lactobacilli, possibly associated with a formerly unveiled esophageal malignancy