Gotowa bibliografia na temat „Spirocyclic molecules”

The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the antihypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century. Actually, there has been a growing interest in the synthesis of heterocyclic hybrids gathered via a spiro carbon. Most of these combinations are two moieties in one scaffold being able to interfere with biological systems through sequential mechanisms. Spirocyclic hybrids containing indole or oxindole units are compounds exhibiting higher interaction with biological receptors by protein inhibition or enzymatic pathways and their recognition as promising anticancer agents in targeted chemotherapy is foreseen. These specific, low-weight and noncomplex spirocyclic hybrids are potent inhibitors of SIRT1, Mdm2–p53 and PLK4, showing affinity for anaplastic lymphoma kinase (ALK) receptor. They are also known as excellent DNA binders, acting on cellular division by arresting the cell cycle at different phases and inducing apoptotic cell death. A structural diversity of spirocyclic hybrids has proved neuroprotective effects, anti-HIV, antiviral and antibacterial activities. Hundred of papers are mentioned in this review underlying chemical issues and pharmacological potencies of spiro compounds, which render them impressive synthetic hits for innovative drug conception.

The concept of spirocyclic restriction as applied broadly to the field of nucleoside mimics makes possible the generation of diastereomeric pairs configured with a syn- or anti-oriented hydroxyl substituent at C5′. The development of concise synthetic routes to spiro-fused nucleosides bearing all possible natural bases and expectedly capable of enforcing a conformation favourable for duplex formation on incorporation into oligomers represents a significant new direction in the design of antisense molecules. The present overview describes the convenient approaches that have been developed in this laboratory for accessing varied members of this class, including analogues that feature sulfur and carbon at the apical position.

The use of fluorescent probes in a multitude of applications is still an expanding field. This review covers the recent progress made in small molecular, spirocyclic xanthene-based probes containing different heteroatoms (e.g., oxygen, silicon, carbon) in position 10′. After a short introduction, we will focus on applications like the interaction of probes with enzymes and targeted labeling of organelles and proteins, detection of small molecules, as well as their use in therapeutics or diagnostics and super-resolution microscopy. Furthermore, the last part will summarize recent advances in the synthesis and understanding of their structure–behavior relationship including novel computational approaches.

<p>We presented the results of acute toxicity and analgesic activity research of the new spirocyclic pyrazolidine-3,5-dione derivatives. We studied the acute toxicity of spirodiazolidines with QSAR analysis by QuS computer design and experimentally on mammalian (mice). These compounds had low toxicity and toxic values that decreased with introduction of methyl substituent in cyclopentenic ring and other substituents in compound aromatic fragments. The acute toxicity values that were obtained by nonexperimental and experimental methods had similar magnitudes, and this will allow to apply the computer prognosis in further investigations and design of new bioactive molecules. We also carried out the research of analgesic activity of new spirocyclic pyrazolidinedione derivatives. We proved that some compounds of the studied range have significant analgesic activity to be competed with well-known pyrazolone containing drug ‘Analgin’.</p>

The Cu-catalyzed multicomponent ketone–amine–alkyne (KA2) reaction was combined with a Pauson–Khand cycloaddition to give access of unprecedented constrained spirocyclic pyrrolocyclopentenone derivatives following a DOS couple-pair approach. The polyfunctional molecular scaffolds were tested on the cyclopentenone reactivity to further expand the skeletal diversity, demonstrating the utility of this combined approach in generating novel spiro compounds as starting material for the generation of chemical libraries. The chemoinformatics characterization of the newly-synthesized molecules gave evidence about structural and physicochemical properties with respect to a set of blockbuster drugs, and showed that such scaffolds are drug-like but more spherical and three-dimensional in character than the drugs.

The possibility of a single-stage solvent-free stereoselective synthesis of a spirocyclic compound from the natural bicyclic monoterpenoid (−)-fenchone and anthranilamide has been shown for the first time. The molecular and crystal structure of (1R,2S,4S)-1,3,3-trimethyl-1′H-spiro[bicyclo[2.2.1]heptane-2,2′-quinazolin]-4′(3′H)-one, C17H22N2O, was established by X-ray diffraction though the chirality was assumed via the known reactant connectivity and 1H and 13C NMR spectroscopy. It has shown that in the molecule, for steric reasons, there is an elongation of the Me2C—C(N)N bond to 1.603 (5) Å. The formation of dimers via N—H...O=C hydrogen bonds with an interaction energy of 93.30 kJ mol−1 and through cavities (33.7% of the unit-cell volume) was established in the packing of the molecules. There are no π-stacking interactions in the structure.

The title compounds, C19H21F3O2S and C24H19F3OS, were prepared via chemo- and regioselective [3 + 2]-cycloadditions of the respective thiocarbonyl ylides (thiocarbonyl S-methanides), generated in situ, with (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one. The thiophene ring in the crystal structure of each compound has an envelope conformation. The largest differences between the two molecular structures is in the bond lengths about the quaternary C atom of the thiophene ring; in the spirocyclic structure, the C—C bonds to the spiro C atom in the cyclobutane ring are around 1.60 Å, although this is also observed in related structures. In the same structure, weak intermolecular C—H...X (X = S, O) interactions link the molecules into extended ribbons running parallel to the [001] direction. In the other structure, weak C—H...π interactions link the molecules into sheets parallel to the (010) plane.

Les contraintes réglementaires des autorités nationales et internationales et les exigences des consommateurs de plus en plus importantes, ainsi que la quête de nouvelles compositions originales, incitent l'industrie de la parfumerie à être constamment à la recherche de nouvelles molécules organoleptiques sûres, durables et innovantes. À cet égard, grâce à la grande diversité du règne végétal, les substances naturelles complexes (SNC), sont une source riche d'ingrédients. Elles sont également une source d'inspiration pour les chimistes, qui peuvent utiliser la synthèse pour avoir un accès contrôlé à des composés d'intérêt (chiralité, quantité suffisante et qualité constante) mais aussi pour préparer des molécules analogues, pouvant générer une amélioration des propriétés olfactives (note et puissance olfactive).Dans ce manuscrit, l'utilisation de la GC-O, complétée par la GC-MS pour l'analyse approfondie du distillat d'une concrète de la plante Ocimum gratissimum est présentée. Cette étude a permis de réaliser la composition chimique de cette extrait, l'identification du chémotype (E)-cinnamate de méthyle, l'évaluation olfactive par un maître-parfumeur ainsi que l'identification des composés odorants importants. Ce manuscrit expose également les stratégies de synthèses asymétriques et multi-étapes investiguées, dans l'objectif d'atteindre les différents énantiomères du vetispira-2(11),6-dien-14-al. En effet, il s'agit d'un composé important de l'huile essentielle d'agarwood, décrit comme ayant une odeur typique du bois d'agar et dont aucune synthèse n'a été publiée à ce jour. Enfin, la mise au point d'une méthodologie d'acétalisation de composés α,β-insaturés, catalysée par FeCl3 est détaillée. Une série de 24 analogues hétérocyliques spiraniques a ainsi été synthétisée et ces composés seront soumis à un maître parfumeur afin d'évaluer leurs notes et pertinence olfactives
The perfumery industry in under constant pressure from national and international regulatory bodies as well and the demands of consumers to produce novel and safe organoleptic molecules via methods which are both durable and innovative. This constant drive for innovation pushes researchers towards diverse domains of the plant kingdom which contains numerous complex natural substances (CNS). At present these natural products are a source of ingredients, however, they are equally a source of inspiration for the chemist who may identify structures of interest to be synthesised with a high degree of control (chirality, quantity, quality, consistency), as well as structural analogues to provide an improvement of the olfactory properties (notes, intensity).This manuscript presents an extended analysis of the distillate of a concrete of the plant Ocimum gratissimum via GC-O complemented with GC-MS analysis. This study has also enlighted the chemical composition of the extract, characterisation of the poorly described (E)-methyl cinnamate chemotype, olfactory evaluation by a master perfumer and the identification of the principal olfactive compounds. This work simultaneously explores multistep asymmetric synthetic strategies in the aim of obtaining the different enantiomers of vetispira-2(11),6-dien-14-al. This compound is known to be an important component of agar wood essential oil and largely responsible for its particular odour. Currently no syntheses of this compound have been published. An FeCl3 catalysed acetylation of α,β-unsaturated compounds was optimised and applied to the synthesis of 24 different heterocyclic spirocycles, which are to be submitted to a master perfumer for the evaluation of their notes and olfactory interest

1. Enantioselective Pd(II)-Catalysed Nucleophilic Additions of 2- Alkylazaarenes The first project deals with enantio- and diastereoselective palladium(II)-catalysed nucleophilic additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes. Under the optimised reaction conditions high levels of diastereo- and enantioselection of the addition products were achieved. Introduction of the electron-withdrawing group at the aryl ring of the substrate allows running the reaction under mild, experimentally convenient reaction conditions. The new described method allows the enantioselective synthesis of 2-(β-aminoalkyl)azaarenes, which are substructures found in drug candidates molecules for the treatment of type 2 diabetes and schizophrenia. 2. Synthesis of Spirocyclic Enones via Rh(III)-Catalysed C–H Functionalisation The second project describes the synthesis of spirocyclic enones by rhodium(III)- catalysed dearomatising oxidative annulation of 2-alkenylphenols with alkynes and 1,3-enynes. A good to high yield with great regioselectivity was obtained. The further synthetic utility of the product was also investigated and led to the formation of highly functionalised tetracycles via 1,6 conjugation addition reaction.

Synthetic and degradable polymers are an attractive choicein many areas, since it is possible to control the way in whichthey are manufactured; more specifically, pathways tomanipulate the architecture, the mechanical properties and thedegradation times have been identified. In this work,L-lactide, 1,5-dioxepan-2-one and ε-caprolactone were usedas monomers to synthesize polymers with different architecturesby ring-opening polymerization. By using novel initiators,triblock copolymers, functionalized linear macromonomers andstar-shaped aliphatic polyesters with well-defined structureshave been synthesized. To synthesize triblock copolymers,cyclic germanium initiators were studied. The polymerizationproceeded in a controlled manner although the reaction rateswere low. To introduce functionality into the polymer backbone,functionalized cyclic tin alkoxides were prepared and used asinitiators. During the insertion-coordination polymerization,the initiator fragment consisting mainly of a double bond wasincorporated into the polymer backbone. The double bond wasalso successfully epoxidized and this gave unique possibilitiesof synthesizing graft polymers with precise spacing. Themacromonomer technique is a very effective method for producingwell-defined graft polymers. Spirocyclic tin initiators weresynthesized and used to construct star-shaped polymers. Thestar-shaped polymers were subsequently crosslinked in apolycondensation reaction. These crosslinked structures swelledin water, and swelling tests showed that by changing thestructure of the hydrogel network, the degree of swelling canbe altered. A first evaluation of the surface characteristicsof the linear triblock copolymers was also performed. AFManalysis of the heat-treated surfaces revealed nanometer-scalefibers and tests showed that keratinocytes were able to growand proliferate on these surfaces.
QC 20100602