Association of liquid-assisted grinding with aging accelerates the inherently slow slipping-on of a dibenzo-24-crown-8 over the N -hydroxysuccinimide ester of an ammonium-containing thread

International audienceSolvent-free and solvent-less slipping-on of the dibenzo-24-crown-8 (DB24C8) over the N-hydroxysuccinimide end of an ammonium-containing thread has been studied and compared to the same reaction operated in solution. Slippage proved to be possible in solvent-free conditions, but the fastest slippage was obtained under heating when preliminary Liquid-Assisted Grinding (LAG) conditions were applied to the reactants followed by aging under an atmosphere of acetonitrile. The recently awarded 2016 Nobel Prize in chemistry 1 has put a light on molecular machines. 2 Some of these machines benet from their interlocked molecular architecture 3 so that the relative displacement of one interlaced element among others becomes possible and controllable. Hence, the straightforward synthesis of interlocked molecules is appealing in order to access novel molecular machines. Using the slippage strategy, 4 we recently reported the preparation of an insulated and stor-able, albeit activated, N-hydroxysuccinimide (NHS) ester-containing [2]rotaxane building block (Scheme 1 and entry 1 of Table 1). 5 This compound is a valuable activated building block for post-interlocking elongation of the encircled axle using bulky amino compounds. 6 As the mechanism of such aminolysis reactions preserves the mechanical bond, it allowed the efficient and straightforward preparation of more sophisticated interlocked compounds such as [2] and [3]rotaxane molecular shuttles. 5,6 Improving the access to the NHS ester-containing [2]rotaxane building block 2 is therefore of real interest. This is particularly justied since in acetonitrile solution , the slipping-on of the DB24C8 (3 equiv.) over the NHS extremity of an ammonium-containing thread (at a concentration of 3 Â 10 À2 M) is very slow and necessitates heating (13 days and 333 K, respectively). In this paper, we wondered if this slipping-on process could be possible, nay improved, by drastically reducing the amount of solvent. Since solvent-free/ solvent-less conditions are highly prone to induce mass transfer limitations, utilisation of ball-milling was envisaged. Indeed it was previously shown that ball-milling could improve the speed of inherently slow reactions. 7 A few examples of solvent-free/solvent-less synthesis of rotaxanes have been reported to date, 8 and to the best of our knowledge, only three of these examples are related to slippage process through a co-melting process 9 or an immediate solvent evaporation method. 10 Herein, different experimental procedures were considered to yield the activated [2]rotaxane 2: solvent-free grinding, 11 Liquid-Assisted Grinding (LAG), 12 and aging by heating with or without an acetonitrile atmosphere. 13 LAG is dened as the use of small amounts of a non-reactive liquid during grinding. 14 It has been shown by us and by other research groups to have a considerable effect on the course of reactions run under mechanical forces. 15 Besides, aging is the action of letting the reaction take place in the absence of any mechanical agitation. This reactivity Scheme 1 Slippage process of the NHS ester-containing molecular axle 1 by the DB24C8

Interlocked building-blocks for Efficients Preparation of Molecular Machinesand Rotaxanes Denied Recognition Site

Cette thèse est dédiée à la conception de synthons entrelacés pour la préparation efficace de machines moléculaires pH-sensible de type rotaxane et de rotaxanes dénués de site de reconnaissance. Bien que la stratégie dirigée par l’effet « template » ait été employée très fréquemment et avec succès à ce jour, elle ne mène dans la plupart des cas qu’à des composés entrelacés qui contiennent les sites d’interactions nécessaires à la reconnaissance préalable des éléments moléculaires à assembler. Pour remédier à cette limitation, une nouvelle voie d’accès directe utilisant des synthons entrelacées pour la préparation de machines moléculaires de type rotaxanes et de rotaxanes dénués de site d’interaction fort a été étudié. Dans un premier temps, des « briques moléculaires » [2]rotaxanes isolables, bien qu’activées, ont été obtenus par une stratégie de glissement. Dans le but de les convertir aisément en machines moléculaires, les paramètres cinétiques et thermodynamiques relatifs au processus d’entrelacement ont été déterminés et ont permis de juger de l’importance de la nature et de l’orientation des pseudo-bouchons sur la cinétique d’entrelacement, ainsi que du rôle primordial du degré de liberté conformationnel de l’axe moléculaire sur la vitesse de formation des rotaxanes. Par la suite, les synthons entrelacées activés sous forme d’ester actif (ester de NHS isolable) sont utilisées dans la préparation de différentes machines moléculaires possédant une station moléculaire principale ammonium et une station moléculaire secondaire triazolium ou amide (secondaire ou tertiaire). D’autres synthons entrelacés qui différent par l’orientation du motif NHS sont utilisé comme transporteurs d’éther couronne pour permettre la préparation de rotaxanes dénués de site d’interaction fort. Enfin, dans la continuité des travaux réalisés au laboratoire sur le contrôle de la conformation chaise d’un mannosyl par une machinerie moléculaire, de nouvelles navettes pH-sensible de type glyco[2]rotaxanes contenant toutes une station moléculaire principale anilinium, et qui différent des machines précédentes par la deuxième station pyridinium, ont été obtenus et étudiés.This thesis is dedicated to the synthesis of interlocked synthons for the efficient preparation of pH-sensitive rotaxane molecular machines and rotaxanes devoid of recognition site. Although the strategy directed by the "template" effect has been used very frequently and successfully so far, in most cases it only leads to interlocked compounds that contain the interaction sites necessary for prior recognition molecular elements to assemble. To overcome this limitation, a new direct access using interlocked synthons for the preparation of molecular machines of the rotaxane and rotaxane type devoid of strong interaction sites has been studied. Firstly, isolable [2]rotaxane "building block", although activated, were obtained by a slipping strategy. In order to easily convert them into molecular machines, the kinetic and thermodynamic parameters relating to the slipping process were determined and made it possible to judge the importance of the nature and orientation of the pseudo-stopper on the kinetics of slipping, as well as the primordial role of the degree of conformational freedom of the molecular axis on the speed of formation of rotaxanes. Subsequently, the activated ester (NHS isolatable ester) interlocked synthon are used in the preparation of different molecular machines having a main ammonium molecular station and a secondary molecular triazolium or amide station (secondary or tertiary). Other interlocked synthons that differ in the orientation of the NHS motif are used as crown ether transporters to enable the preparation of rotaxanes devoid strong interaction sites. Finally, in the continuity of the work carried out in the laboratory on the control of the chair conformation of a mannosyl by a molecular machinery, new pH-sensitive shuttles of glyco[2]rotaxane containing a main molecular station anilinium, and which different previous machines by the second station pyridinium, were obtained and studied

Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements

International audienceThe synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units

Reverse Anomeric Effect in Large-Amplitude Pyridinium Amide-Containing Mannosyl [2]Rotaxane Molecular Shuttles

International audienceThe reverse anomeric effect (RAE) was investigated in different mannosyl [2]rotaxane molecular shuttle isomers that contain dibenzo-24-crown-8 (DB24C8) as the macrocycle, and anilinium and pyridinium amide as molecular stations. The switching on or off of the RAE was possible depending on both the pyridinium amide motif and the localization of the DB24C8 along the thread. The 1C4 mannopyranosyl chair-like conformation was observed in all the non-interlocked molecules because the anomeric carbon of the mannose is linked to the positively charged nitrogen of the pyridinium unit. In the protonated rotaxanes, the 1C4 chair conformation of the mannose end remains because the DB24C8 resides around the best anilinium station, which is located at the other end of the axle. Upon deprotonation of the anilinium, the DB24C8 shuttles with a large-amplitude motion toward the pyridinium amide stations, where it interacts in a different fashion depending on the pyridinium motif. In one molecular shuttle, the RAE could be switched on or off with control at one end of the encircled thread upon protonation/deprotonation of the other end, through shuttling of the DB24C8

Synthesis of a pH-Sensitive Hetero[4]Rotaxane that Combines [c2]Daisy and [2]Rotaxane Arrangements

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How Secondary and Tertiary Amide Moieties are Molecular Stations for Dibenzo-24-crown-8 in [2]Rotaxane Molecular Shuttles?

Interlocked molecular machines like [2]rotaxanes are intriguing aesthetic molecules. The control of the localization of the macrocycle, which surrounds a molecular axle, along the thread leads to translational isomers of very different properties. Although many moieties have been used as sites of interactions for crown ethers, the very straightforwardly obtained amide motif has more rarely been envisaged as molecular station. In this article, we report the use of secondary and tertiary amide moieties as efficient secondary molecular station in pH-sensitive molecular shuttles. Depending on the N-substitution of the amide station, and on deprotonation or deprotonation-carbamoylation, the actuation of the molecular machinery differs accordingly to very distinct interactions between the axle and the DB24C8

Bioorthogonal drug release from nanometric micelles in living cells

International audienceAbstract We explored a bioorthogonal approach to release drugs from stimuli‐responsive micelles inside tumor cells. The concept relies on sydnonimine‐based micelles that undergo quantitative cleavage in presence of cyclooctynes, hence releasing their content within living cells. Four cleavable micelles were developed to allow massive burst release of Entinostat, a potent histone deacetylase inhibitor, following their internalization inside cancer cells. A comparative study on the influence of the bioorthogonal‐mediated versus passive drug release from micelles was carried out. The results indicated that a fast release of the drug triggered a stronger antiproliferative activity on tumor cells compared to the passive diffusion of the drug from the micelles core. These finding may be of great interest for the development of new nanomedicines

Combination of Targeted Therapies for Colorectal Cancer Treatment

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