Synthesis of natural maleimides farinomaleins C–E and evaluation of their antifungal activity

A practical and convenient synthesis of naturally occurring farinomaleins C\u2013E was achieved starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate. The key steps of the sequence included a Horner\u2013Wadsworth\u2013Emmons condensation to obtain the precursor farinomalein A and coupling with suitable alcohols to install the chain. The synthesis of farinomalein D has been achieved starting from (R)-isopropylideneglycerol on the basis of which the S configuration was assigned to the natural compound. The antifungal activity of the synthesized compounds was evaluated against Cladosporium cladosporioides

Perspectives in the development of hybrid bifunctional antitumour agents

In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents

Total synthesis of tetracyclic kynurenic acid analogues isolated from chestnut honey

A short and efficient synthesis of novel tetracyclic Kynurenic acid analogues, isolated from chestnut honey, is described. The crucial step of the strategy was a MW-assisted cyclization of enamines of ethyl dioxohexahydropyrrolizine and 2,3-dioxooctahydroindolizine carboxylates to obtain 2,3,6,11b-tetrahydro-1H-pyrrolizino[2,1-b]quinoline-5,11-dione and 5,8,91,011,11a-hexahydroindolizino[2,1-b]quinoline-6,12-dione, respectively. Because of its modular nature, the synthetic strategy can have value as a general method for the preparation of compounds containing these new heterocyclic scaffolds

4-Quinolone fused heterocyclic ring systems by intramolecular reactions of 4-quinolone-2-carboxamides

A versatile synthetic route to new 4-quinolone-based polycyclic systems is described. TFA-catalyzed intramolecular reaction of N-unsubstituted quinolone-2-carboxylic acid amides gives structurally diverse compounds, depending on the length of the chain. Acid treatment of \u3b2-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas TFA treatment of \u3b4- and \u3b5-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction

New antimicrobials based on the adarotene scaffold with activity against multi-drug resistant staphylococcus aureus and vancomycin-resistant enterococcus

The global increase in infections by multi-drug resistant (MDR) pathogens is severely impacting our ability to successfully treat common infections. Herein, we report the antibacterial activity against S. aureus and E. faecalis (including some MDR strains) of a panel of adarotene-related synthetic retinoids. In many cases, these compounds showed, together with favorable MICs, a detectable bactericidal effect. We found that the pattern of substitution on adarotene could be modulated to obtain selectivity for antibacterial over the known anticancer activity of these compounds. NMR experiments allowed us to define the interaction between adarotene and a model of microorganism membrane. Biological assessment confirmed that the scaffold of adarotene is promising for further developments of non-toxic antimicrobials active on MDR strains

Total synthesis of the salicyldehydroproline-containing antibiotic promysalin

A convergent total synthesis of promysalin, a metabolite of Pseudomonas putida RW10S1 with antibiotic activity, is described. The synthetic approach is based around a salicyldehydroproline core and a dihydroxymyristamide fragment. Crucial steps include a MacMillan asymmetric \u3b1-hydroxylation applied for the construction of the myristamide framework, and a lactam reduction by Superhydride\uae to obtain the dehydroproline fragment. Because of the modular nature of the synthesis, ready access to analogues for biological evaluation is available

An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches

Samarium iodide-promoted asymmetric Reformatsky reaction of 3-(2-Haloacyl)-2-oxazolidinones with enals

3-(2-Haloacyl)-2-oxazolidinones were shown to react with enals in an asymmetric SmI2-promoted Reformatsky reaction to give stereochemically well-defined 3-hydroxy-4-alkenyl- and 3-hydroxy-2-methyl-4-alkenyl imides. Chirality transfer of the Evans (S)-oxazolidinone unit via a Zimmerman-Traxler-like transition state resulted in Reformatsky products with a relative syn-configuration. The absolute configuration of compounds obtained is opposite to the corresponding products obtained via aldol addition of boron enolates to enals using the same Evans oxazolidinones

The Garisenda Tower in Bologna: Effects of degradation of selenite basement on its static behaviour

The Garisenda tower in Bologna, a 48 m tall structure with a square base of 7.45 meters per side, is characterized by an overall out of plumb of 3.32m in the South-East direction. Its construction dates back to the XI century and, due to its impressive leaning, in 1350–1353 the original height of 60m was reduced to the 48m of the present day (Cavani 1903; Giordano 2000). The tower can be seen as partitioned in a lower portion, with walls composed by two external leaves of selenite stones filled with rubble conglomerate, and an upper portion where the external leaves are made of masonry bricks. Recent investigations have proved that selenite blocks of the basement have been altered as a result of (a) exposition to high temperatures during important fires, that took place at the end of XIV and XVII centuries, and possibly because of the presence of forges (that were demolished at the end of the XIX centuries) and (b) high level of humidity in the inner lower part of the tower. This process has produced a gradual local disintegration of the selenite stones, leading in some case to a reduction of the original 50 to 60 cm thickness by an amount of about 20 cm. The contribution submitted to this conference is aimed at clarifying this important aspect, linked to the ageing and damage of structural stones and the related consequences in terms of stress distribution and concentrations that could induce fracture propagation and sudden collapse of the tower basement