RESUMEN
The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.
Asunto(s)
Antineoplásicos , Apoptosis , Microtúbulos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Línea Celular Tumoral , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Estereoisomerismo , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos , OxazolesRESUMEN
The design of pyridine-derived organocatalysts aims at the increase of their Lewis basicity, however such an approach is not always efficient. For example, strongly Lewis basic DMAP is completely inefficient as catalyst in the cyclopropanation reaction. Herein we disclose an alternative approach that relies on attenuation of DMAP Lewis basicity. Specifically, the replacement of 4-dimethylamino substituent in DMAP for 4-MeO group delivered a highly efficient catalyst for cyclopropanation of electron-deficient olefins with α-bromoketones. Kinetic studies provide compelling evidence that the superior catalytic efficiency of 4-MeO pyridine (MOPY) is to be attributed to the favorable balance between Lewis basicity and leaving group ability. The use of chiral, enantiomerically pure MOPY catalyst has helped to achieve high enantioselectivities (up to 91 : 9 er) in the previously unreported pyridine-catalyzed cyclopropanation reaction.
RESUMEN
Cationic luminophores have recently emerged as a class of efficient emitters in both the solid state and solutions. However, the underlying processes that secure the emission in these luminophores are poorly understood. Here, we employ charge transfer integral (CTI) analysis in combination with X-ray single crystal data to uncover the emission mechanism in a series of pyridinium luminophores. We demonstrate that the solid state photoluminescence quantum yield (Φ) of cationic luminophores is directly proportional to the charge transfer (CT) intensity within a network of molecules in the crystal lattice. Electrostatic intermolecular interactions between π+-systems in the crystal lattice provide a disproportionately high contribution to the CT intensity and therefore are instrumental in achieving high Φ. In addition, the strength of electrostatic interactions can be increased by a through-space (TS) electron-donation strategy. Hence, electrostatic interactions can be utilized as a tool to achieve radiative CT, which is useful in the development of efficient luminophores, sensors and nonlinear optical materials.
RESUMEN
Herein we report an approach for the straightforward preparation of fluorocyclopropylidene group from aldehydes and ketones via Julia-Kocienski olefination using the newly developed reagent 5-((2-fluorocyclopropyl)sulfonyl)-1-phenyl-1H-tetrazole. Derivatization of monofluorocyclopropylidene compounds includes hydrogenation to deliver fluorocyclopropylmethyl compounds and fluorinated cyclobutanones. The utility of the described method is demonstrated by the synthesis of a fluorocyclopropyl-containing analogue of ibuprofen. Bioisosteric replacement of isobutyl with the fluorocyclopropyl group may be used for tuning biological properties of drug molecules.
RESUMEN
Liquid SO2 is a polar solvent that dissolves both covalent and ionic compounds. Sulfur dioxide possesses also Lewis acid properties, including the ability to covalently bind Lewis basic fluoride ions in a relatively stable fluorosulfite anion (FSO2 -). Herein we report the application of liquid SO2 as a promoting solvent for glycosylation with glycosyl fluorides without any external additive. By using various temperature regimes, the method is applied for both armed and disarmed glucose and mannose-derived glycosyl fluorides in moderate to excellent yields. A series of pivaloyl-protected O- and S-mannosides, as well as one example of a C-mannoside, are synthesized to demonstrate the scope of the glycosyl acceptors. The formation of the fluorosulfite species during the glycosylation with glycosyl fluorides in liquid SO2 is proved by 19F NMR spectroscopy. A sulfur dioxide-assisted glycosylation mechanism that proceeds via solvent separated ion pairs is proposed, whereas the observed α,ß-selectivity is substrate-controlled and depends on the thermodynamic equilibrium.
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Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Bäckvall's ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation-π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.
Asunto(s)
Rutenio , Alcoholes , Catálisis , Cinética , EstereoisomerismoRESUMEN
Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.
RESUMEN
The use of non-covalent intermolecular π+-π interactions between quaternary pyridinium or imidazolium cations and aromatic π systems is an efficient approach to achieve AIE in planar purely organic luminophores.
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A scalable synthesis of chiral Vedejs-type DMAP catalysts is reported. The key step of the synthesis is amination of the enantiomerically pure 4-chloropyridine derivative using well-defined ZnCl2(amine)2 complexes. A series of Zn(II)-amine complexes have been synthesized to explore the scope of the ZnCl2-mediated amination of 4-halopyridines. Mechanistic studies support a Zn(II)-facilitated nucleophilic aromatic substitution as a plausible mechanism for the chlorine-to-amine exchange.
RESUMEN
A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the tert-leucinol-derived chiral subunit of DMAP species.
RESUMEN
Disubstituted allylic bis-imidates undergo Lewis acid catalyzed or spontaneous cyclization to oxazolines, which are precursors of unsaturated amino alcohols. Stereoselectivity of the cyclization is mainly determined by the substrate configuration. Highly selective cis-oxazoline formation is achieved starting from anti-E-bis-imidates while trans-oxazoline predominantly forms from anti-Z-bis-imidates. On the basis of DFT calculations, the stereoselectivity trends can be explained by the formation of the energetically most stable carbenium ion conformation, followed by the cyclization via most favorable bond rotations.