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1.
Mandlenkosi Robert Khumalo Surya Narayana Maddila Suresh Maddila Sreekantha B. Jonnalagadda 《RSC advances》2019,9(53):30768
A facile, swift and ecofriendly microwave-assisted multi-component/one-pot protocol is designed for the synthesis of novel pyrazolo-[3,4-b]-quinolines at ambient temperature in aqueous ethanol as a reaction medium. The 18 novel pyrazolo-[3,4-b]-quinoline derivatives were synthesized by fusion of chosen aryl aldehyde, dimedone and 5-amino-3-methyl-1-phenylpyrazole in excellent yields (91–98%). All the molecular structures were confirmed by 1H-NMR, 15N-NMR, 13C-NMR, and HRMS data analysis. Operational simplicity, easy handling, one-step simple workup procedure, mild reaction conditions, short reaction time (≤10 min), high selectivity and no by-product formation are the striking features of the protocol.A facile, swift and ecofriendly microwave-assisted multi-component/one-pot protocol is designed for the synthesis of novel pyrazolo-[3,4-b]-quinolines at ambient temperature in aqueous ethanol as a reaction medium. 相似文献
2.
Ibrahim F. Nassar Mohammed T. Abdel Aal Wael A. El-Sayed Mahmoud A. E Shahin Elsayed G. E. Elsakka Mahmoud Mohamed Mokhtar Maghawry Hegazy Mohamed Hagras Asmaa A. Mandour Nasser S. M. Ismail 《RSC advances》2022,12(23):14865
CDK2 inhibition is an appealing target for cancer treatment that targets tumor cells in a selective manner. A new set of small molecules featuring the privileged pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds. The growth of the three examined cell lines was significantly inhibited by most of the prepared compounds. Results revealed that most of the compounds showed superior cytotoxic activities against MCF-7 and HCT-116 with IC50 range (45–97 nM) and (6–99 nM), respectively, and moderate activity against HepG-2 with IC50 range of (48–90 nM) compared to sorafenib (IC50: 144, 176 and 19 nM, respectively). Of these compounds, 14 & 15 showed the best cytotoxic activities against the three cell lines with IC50 values of 45, 6, and 48 nM and 46, 7, and 48 nM against MCF-7, HCT-116 and HepG-2, respectively. Enzymatic inhibitory activity against CDK2/cyclin A2 was achieved for the most potent anti-proliferative compounds. Compounds 14, 13 and 15 revealed the most significant inhibitory activity with IC50 values of 0.057 ± 0.003, 0.081 ± 0.004 and 0.119 ± 0.007 μM, respectively compared to sorafenib (0.184 ± 0.01 μM). Compound 14 displayed potent dual activity against the examined cell lines and CDK2, and was thus selected for further investigations. It exerted a significance alteration in cell cycle progression, in addition to apoptosis induction within HCT cells. Molecular docking simulation of the designed compounds confirmed the good fit into the CDK2 active site through the essential hydrogen bonding with Leu83. In silico ADMET studies and drug-likeness studies using a Boiled Egg chart showed suitable pharmacokinetic properties which helped in structure requirement prediction for the observed antitumor activity.A new set of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds. 相似文献
3.
Green synthesis of pyrazolo[3,4-b]quinolinones was designed using bioproduct pyridine-2-carboxylic acid (P2CA) as a green and efficient catalyst. The multi-component reaction of aldehydes, 1,3-cyclodiones and 5-amino-1-phenyl-pyrazoles regioselectively produced pyrazolo[3,4-b]quinolinones in excellent yield (84–98%). Recyclization of the catalyst was also investigated. The electronic effect of the various substituents in aromatic rings indicated that the reaction proceeded through the carbocation intermediate. This newly designed protocol very quickly constructed products conventionally under milder conditions.Green synthesis of pyrazolo[3,4-b]quinolinones was designed using bioproduct pyridine-2-carboxylic acid (P2CA) as a green and efficient catalyst. 相似文献
4.
Abdullah Mohammed Al-Majid Abdullah Saleh Alammari Saeed Alshahrani Matti Haukka Mohammad Shahidul Islam Assem Barakat 《RSC advances》2022,12(10):6149
The highly efficient Lewis acid-catalytic system Cu(ii)-thiophene-2,5-bis(amino-alcohol) has been developed for enantioselective Aldol reaction of isatin derivatives with ketones. The new catalytic system also proved to be highly enantioselective for the one pot three-component Domino Knoevenagel Michael cyclization reaction of substituted isatin with malononitrile and ethylacetoacetate. The chiral ligand (2S,2′S)-2,2′-((thiophene-2,5-diylbis(methylene))bis(azanediyl))bis(3-phenylpropan-1-ol) (L1) in combination with Cu(OAc)2·H2O employed as a new Lewis acid catalyst, furnished 3-substituted-3-hydroxyindolin-2-ones derivatives (3a–s) in good to excellent yields (81–99%) with high enantioselectivities (up to 96% ee) and spiro[4H-pyran-3,3-oxindole] derivatives (6a–l) in excellent yields (89–99%) with high ee (up to 95%). These aldol products and spiro-oxindoles constitute a core structural motif in a large number of pharmaceutically active molecules and natural products.The highly efficient Lewis acid-catalytic system Cu(ii)-thiophene-2,5-bis(amino-alcohol) has been developed for enantioselective Aldol reaction of isatin derivatives with ketones. 相似文献
5.
A versatile and substrate oriented multicomponent reaction for the syntheses of novel highly diastereoselective tetrahydro-1′H-spiro[pyrazolo[4,3-f]quinoline-8,5′-pyrimidine]-2′,4′,6′(3′H)-triones (d.r. up to 20 : 1 (syn : anti)) and tetrahydro-8H-pyrazolo[4,3-f]pyrimido[4,5-b]quinoline-8,10(9H)-diones via formation of selective multiple C–C bonds under identical reaction conditions (viz. ethanol as a reaction medium and deep eutectic mixture as a catalyst) is demonstrated. Both approaches involve mild reaction conditions, use of non-hazardous solvents, and facilitate good to excellent reaction yields of the target compounds.Substrate selectivity in the novel multi-component reaction of 5-aminoindazole, barbituric acid derivatives and aldehyde is explored. 相似文献
6.
R. Belaroussi A. Ejjoummany A. El Hakmaoui M. Akssira G. Guillaumet S. Routier 《RSC advances》2018,8(2):732
The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. 相似文献
7.
A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.Spiropyrrolidine-oxindole grafted and bis-spiropyrrolizidine-oxindole grafted macrocyles with triazole as a spacer unit have been achieved via regioselective and stereoselective intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides (click reaction). 相似文献
8.
An efficient, cost-effective, transition-metal-free, oxidative C(sp2)–H/C(sp2)–H cross-dehydrogenative coupling via a C(sp2)–H bond functionalization protocol for the regioselective direct C-3 acylation/benzoylation of substituted 2H-Indazoles 1a–m with substituted aldehydes 2a–q/benzyl alcohols 5a–e/styrenes 6a–e is reported. The operationally simple protocol proceeds in the presence of tert-butyl peroxybenzoate (TBPB) as an oxidant in chlorobenzene (PhCl) as a solvent at 110 °C for 24 h under an inert atmosphere, which furnished a diverse variety of substituted 3-(acyl/benzoyl)-2H-indazoles 3a–q/4a–l in up to 87% yields. The reaction involves a free-radical mechanism and proceeds via the addition of an in situ generated acyl radical (from aldehydes/benzyl alcohols/styrenes) on 2H-indazoles. The functional group tolerance, broad substrate scope, control/competitive experiments and gram-scale synthesis and its application to the synthesis of anti-inflammatory agent 11 and novel indazole-fused diazepine 13 further signify the versatile nature of the developed methodology.An efficient transition-metal-free oxidative C(sp2)–H/C(sp2)–H cross-dehydrogenative coupling via C(sp2)–H bond functionalization for regioselective C-3 acylation/benzoylation of 2H-indazoles with aldehydes/benzyl alcohols/styrenes is reported. 相似文献
9.
Herein, we report a methodology for constructing mechanically self-locked molecules (MSMs) through the efficient intramolecular copper(i)-catalyzed alkyne–azide cycloaddition (CuAAC) of self-threaded A1/A2-azido-propargyl-difunctionalized pillar[5]arenes. The obtained monomeric “pseudo[1]catenane” and dimeric “gemini-catenane” were isolated and fully characterized using mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, and X-ray crystallography. Upon investigation by 1H NMR spectroscopy in chloroform, the observed motion for the threaded ring in the pseudo[1]catenane was reversibly controlled by the temperature, as demonstrated by variable-temperature 1H NMR studies. Two gemini-catenane stereoisomers were also isolated in which the two pillar[5]arene moieties threaded by two decyl chains were aligned in different topologies. Furthermore, the conformational inversion of pseudo[1]catenane and the gemini-catenanes triggered by solvents and guests was investigated and probed using 1H NMR spectroscopy, isothermal titration calorimetry, and single-crystal X-ray analysis.Mechanically self-locked molecules (MSMs) through the efficient intramolecular copper(i)-catalyzed alkyne–azide cycloaddition (CuAAC) of self-threaded A1/A2-azido-propargyl-difunctionalized pillar[5]arenes. 相似文献
10.
A practical synthesis of diarylpyrazolo[3,4-b]pyridine derivatives by a combination of chemoselective Suzuki–Miyaura cross-coupling reactions was developed. The sequential arylation strategy can be performed in a one-pot manner without much loss of efficiency when compared to the corresponding stepwise synthesis. These conditions are applicable to the coupling of a wide variety of aryl and heteroaryl-boronic acids with pyrazolo[3,4-b]pyridines with high selectivity of the C3 over the C6 position, thus enabling the rapid construction of a diverse array of medicinally important diarylpyrazolo[3,4-b]pyridines.An efficient method to produce diarylpyrazolo[3,4-b]pyridines derivatives via combination of chemoselective Suzuki–Miyaura cross-coupling reactions has been developed. 相似文献
11.
A highly convenient and sustainable one-pot approach for the diversely-oriented synthesis of a variety of medicinally privileged amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives on the basis of a domino three-component reaction of readily available carbonyl compounds including aryl aldehydes or isatins, active methylene compounds, and kojic acid as a Michael donor using secondary amine catalyst l-proline under ultrasound irradiation in aqueous ethanolic solution at ambient temperature has been developed. This methodology can involve the assembly of C–C, C C, C–O, C–N bonds via a one-pot operation, and following this protocol, a series of novel amino-substituted spiro[indeno[1,2-b]quinoxaline-11,4-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylates have been synthesized. The practical utility of this method was found to be very efficient for scale-up reaction and other useful transformations. The methodology provides significant advantages including mild reaction conditions, energy-efficiency, short reaction time, fast reaction, simple work-up procedure, broad functional group tolerances, utilization of reusable catalyst, green solvent system, being metal-free, ligand-free, waste-free, inexpensive, etc. Excellent chemical yields have been achieved without using column chromatography. To address the issues of green and more sustainable chemistry, several metrics including Atom Economy (AE), Reaction Mass Efficiency (RME), Atom efficiency, E-factor, Process Mass Intensity (PMI), and Carbon Efficiency (CE) have been quantified for the present methodology that indicates the greenness of the present protocol.Amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives has been synthesised under ultrasound irradiation in aqueous ethanolic solution at rt. 相似文献
12.
Ahmad Seif Luis R. Domingo Ehsan Zahedi Temer S. Ahmadi Elham Mazarei 《RSC advances》2020,10(54):32730
The kinetic and electron density flows are studied theoretically for the gas phase pyrolysis of cubane via its cage opening to reach bicyclooctatriene and then thermal rearrangement of bicyclooctatriene to produce [8]annulene which is the experimentally observed major product. The observed kinetic data at the MN15-L/maug-cc-pVTZ level of theory were in good agreement with the experimental results as compared to the CBS-QB3 method. The cage opening and the thermal rearrangement steps at the experimentally employed temperature of 520 K were exergonic and exothermic. The atmospheric rate constants calculated by means of the RRKM theory show that the cage opening is the rate-determining step. The temperature dependence of the rate constant for the cage opening step at the MN15-L level can be expressed as log(k/s−1)1barMN15-L = (15.63) − (48.99 kcal mol−1)/RT ln 10. The molecular mechanism of the reactions has been investigated by means of the bonding evolution theory (BET) at the B3LYP/6-311G (d,p) level of theory. The cage opening course is described topologically by cleaving of C1–C2, C4–C8, and C5–C6 single bonds and electron saturation of the C1–C4, C2–C6, and C5–C8 bonds, while the rearrangement of bicyclooctatriene is described by C3–C7 bond rupture, depopulation of C1–C4 and C5–C8 double bonds, and electron saturation of C1–C5, C3–C4, and C7–C8 bonds. Electron density rearrangement along the two successive steps are asynchronous and the sequence of catastrophes can be represented as: η-1-13-C†C†FFFC†C†FFFC†C†-2-6-[C]2C†[F]2[C†]2C†-0.Kinetic and electron density flows are studied theoretically for the gas phase pyrolysis of cubane via its cage opening to bicyclooctatriene and then thermal rearrangement of bicyclooctatriene to produce [8]annulene which is the experimentally observed major product. 相似文献
13.
PEG-400 has been used as a green and biodegradable polymeric solvent for the one-pot, two-step, multi-component synthesis of novel asymmetrical bis-spirooxindole derivatives by the reaction of N-alkyl isatin, isatin derivatives, alkylmalonates and C–H activated carbonyl compounds in the presence of K2CO3 at room temperature. Using this procedure, all the products were obtained in good to excellent yields.PEG-400 has been used for the synthesis of novel asymmetrical bis-spirooxindoles by the reaction of N-alkyl isatin, isatin derivatives, alkylmalonates and C–H activated carbonyl compounds in the presence of K2CO3 at room temperature. 相似文献
14.
Nicu-Cosmin Ostache Marie-Aude Hiebel Adriana-Luminia Fînaru Hassan Allouchi Grald Guillaumet Franck Suzenet 《RSC advances》2021,11(16):9756
Despite the pharmacological potential of the pyrazolo[3,4-c]pyrazoles, only a few methods of preparation and direct functionalization of this moiety have been described. We report herein a convenient design of new pyrazolo[3,4-c]pyrazoles with a high therapeutic impact. The effective chosen strategy consists of hydrazine condensations and C–N Ullmann-type cross-coupling reactions with microwave activation. Moreover, chemoselective bromination of the newly formed bipyrazoles followed by Suzuki–Miyaura cross-coupling reactions allowed the synthesis of a variety of modulated heterobicycles.A convenient design of pyrazolo[3,4-c]pyrazoles is reported through hydrazine condensations and C–N Ullmann-type cross-coupling reactions. Chemoselective bromination followed by Suzuki–Miyaura cross-coupling reactions access to a variety of modulated heterobicycles. 相似文献
15.
Yuki Murata Saori Tsuchida Rena Nezaki Yuki Kitamura Mio Matsumura Shuji Yasuike 《RSC advances》2022,12(23):14502
Herein, we describe a simple and general multi-component synthesis of 5-arylselanyluracils by the regioselective C–H selenation of uracils. Reactions of uracils with arylboronic acid and Se powder in the presence of AgNO3 (10 mol%) at 120 °C under aerobic conditions afforded various 5-arylselanyluracils. The source of the introduced selanyl group was prepared from a commercially available arylboronic acid and Se powder in the reaction system, thereby ensuring a simple and efficient protocol. This reaction represents the first example of the synthesis of a 5-arylselanyluracil in a multi-component system.A simple and general multicomponent synthesis of 5-arylselanyluracils by regioselective C–H selenation of uracils is described. 相似文献
16.
Alexis Tigreros Sandra-L. Aranzazu Nestor-F. Bravo Jhon Zapata-Rivera Jaime Portilla 《RSC advances》2020,10(65):39542
Fluorescent molecules are crucial tools for studying the dynamics of intracellular processes, chemosensors, and the progress of organic materials. In this study, a family of pyrazolo[1,5-a]pyrimidines (PPs) 4a–g has been identified as strategic compounds for optical applications due to several key characteristics such as their simpler and greener synthetic methodology (RME: 40–53%) as compared to those of BODIPYS (RME: 1.31–17.9%), and their tunable photophysical properties (going from ε = 3320 M−1 cm−1 and ϕF = 0.01 to ε = 20 593 M−1 cm−1 and ϕF = 0.97), in which electron-donating groups (EDGs) at position 7 on the fused ring improve both the absorption and emission behaviors. The PPs bearing simple aryl groups such as 4a (4-Py), 4b (2,4-Cl2Ph), 4d (Ph) and 4e (4-MeOPh), allow good solid-state emission intensities (QYSS = 0.18 to 0.63) in these compounds and thus, solid-state emitters can be designed by proper structural selection. The properties and stability found in 4a–g are comparable to commercial probes such as coumarin-153, prodan and rhodamine 6G. Ultimately, the electronic structure analysis based on DFT and TD-DFT calculations revealed that EDGs at position 7 on the fused ring favor large absorption/emission intensities as a result of the ICT to/from this ring; however, these intensities remain low with electron-withdrawing groups (EWGs), which is in line with the experimental data and allows us to understand the optical properties of this fluorophore family.A family of 7-aryl-3-methylpyrazolo[1,5-a]pyrimidines have been identified as strategic compounds for optical applications by a comprehensive theoretical-experimental study. 相似文献
17.
A reversible pseudo-single-ligand-gated ion transportation switch of ON–OFF–ON type was achieved through host–guest complexation with pillar[6]arene (P[6]) as the ion channel, and a photoresponsive azobenzene as the dual-role (open and close) ligand.A reversible pseudo-single-ligand-gated ion transportation switch of ON–OFF–ON type through pillar[6]arene and photoresponsive azobenzene as dual-role ligand.Stimuli-responsive synthetic transmembrane channels have attracted much attention due to their broad applications, such as molecular recognition, drug delivery and functional nanodevices.1,2 Various stimuli including potential, mechanical force, light, and ligand have been utilized in this field.3,4 Amongst these, ligand gating is one of the typical approaches. So far, limited synthetic ligand-gated channels have been reported.4–7 Most of such channels are operated merely in an irreversible manner, i.e. the channels are either opened or blocked upon the addition of stimuli ligands, achieving the OFF–ON or ON–OFF behavior.8–11 However, synthetic channels with a reversible ligand-gating capability, which exist widely in nature, are much more fascinating because of their much more extensive applications. Only a few reversible switches of OFF–ON–OFF type have been reported.3 Those examples are featured with the successive introduction of two guests; the first one is to trigger the formation of channels (host), realizing the OFF–ON capability; and then introduction of the second one is to disrupt the channeling capability, realizing the transformation from ON to OFF states.12–14 However, the reversible ligand-gated switches of ON–OFF–ON type have not been reported yet, except for the only one reported by our group;15 the switch featured with calix[6]arene (CX6) as the channel, methylene blue (MB) as the channel blocker, and 4-sulfonated calix[6]arene with stronger affinity for MB as the channel-opener. However, all the reversible ligand-gating switches reported, thus far, require successive introduction of two extra components to realize the transformations either from ON to OFF then back to ON states, or from OFF to ON then back to OFF states. Obviously, limited repetition numbers of such bi-component-gating switches are foreseeable due to the accumulation of intruders, leading to the disruption of the labile membrane.16 Noninvasive photoresponsive ligand-gating switch should have prolonged durability. To the best of our knowledge, Gin''s group and Woolley''s group reported the only two examples of such switch, which was of OFF–ON–OFF type and synthesized through elaborate route.17,18 However, photoresponsive ligand-gating switch of ON–OFF–ON type has not been reported yet.Pillar[n]arenes are a class of host cavitands and have been widely studied.19–22 Herein, we reported a reversible “single-molecule ligand-gating switch” of ON–OFF–ON type by using commercial available unmodified P[6] (pillar[6]arene) as the ion channel and readily obtainable azobenzene molecule as the photoresponsive gating ligand. Though the channeling capabilities of pillararene derivatives, and the host–guest behavior of P[6] with the cis-/trans-isomers of azobenzene have been reported previously.23,24 There are still some questions to be answered.21 First is the channeling activity mediated by internal or external cavities of pillararenes; second, whether the guest molecules will affect channel activity or rupture the membrane or not; finally, whether the host and guest molecules will still associate/dissociate efficiently in lipid bilayer membrane similar as they are in solution thereby realizing multiple recurring applications of “single-molecule ligand-gating switch”.The transmembrane channeling capability of unmodified P[6] has not been studied yet, which was examined firstly by using HPTS (a pH sensitive fluorescence dye) entrapped LUVs (large unilamellar vesicles).25 Firstly, the pH gradient was establish by using a intravesicular aqueous buffer solution at pH 7.0 and an extravesicular aqueous buffer solution at pH = 7.6. Then, upon addition of P[6] solution in THF into the HPTS-encapsulated LUVs suspension, the fluorescence emission was recorded immediately until 1800 s. Finally, Triton X-100 (a surfactant) was added to disrupt LUVs and achieve the maximal fluorescence emission as the 100% reference point. As shown in Fig. 1A, a rapid increase of HPTS fluorescence emission was observed upon the introduction of P[6], which reaches 90% of the maximal level within 1800 s. This result indicates the increase of intravesicular pH through proton efflux or OH− influx in response to the transmembrane pH gradient (ΔpH = 0.6). Very small increase (≤10%) of fluorescence emission was observed in control experiment in the absence of P[6] (Fig. 1A), suggesting that P[6] is indeed responsible for the observed fluorescence increase. Furthermore, we examined the concentration dependence of channel activities of P[6]. As shown in Fig. 1A, the proton transport activity of P[6] is concentration dependent. When the concentration dropped to 5 μM, the activity can still reach to 83%. Even if the concentration is as low as 1 μM, the channelling efficiency still could remain 46%. Such activity of P[6] is comparable to many reported synthetic ion channels, including calixs and phenylene vinylene macrocycles in our previous reports.15,26 The above experimental results shows that the unmodified P[6] is able to serve as an efficient transmembrane ion channel. Such activity of P[6] is comparable to the reported ion channels composed of modified pillararenes, if not better.25Open in a separate windowFig. 1(A) Normalized HPTS fluorescence traces as a function of time in the presence of P[5] (10 μM), P[6]–tBu (10 μM) and P[6] with various concentrations (1–10 μM). The concentration of the pillararene in total lipids was 10 μM. (B) Normalized fluorescence traces of calcein assay in the presence (red line) or absence (black line) of P[6] (10 μM).Then, we explored the channel activity influence of internal cavity using P[5] and P[6]–tBu (pillar[5]arenes and tert-butyl substituted pillar[6]arenes) by same assays. Higher activity was observed with P[6] containing larger cavity size (∼0.67 nm) while P[5] with smaller cavity size (∼0.47 nm) shows moderate HPTS fluorescence emission (around 65%) increase even extended incubation period.27 The impaired activity of P[5] may be due to the reduced cavity size leading to slowdown proton efflux. Furthermore, P[6]–tBu shows almost negligible fluorescence increase which is close to the blank experiment. The shutdown transportation of P[6]–tBu may be owing to that the tert-butyl groups located on the entrance of channel internal cavity may induce static hindrance and thus prohibiting proton efflux.In order to confirm the ion transportation through the interior cavity of P[6], we examined the transportation disability of a larger fluorescence dye-calcein to rule out the transportation possibility from outside of the cavity. The hydrated radius of calcein is about 0.8 nm which is more than twice that of internal cavity of P[6].28 Therefore, calcein could not be transported from the cavity of P[6]. The calcein-encapsulated LUVs (∼40 mM) were prepared for calcein assay. Very minor increase of fluorescence intensity was observed after addition of P[6], even the concentration was up to 10 μM, which was only increased to 24%. The negligible increase was close to the controlling experiment showing no leakage of calcein from LUVs, indicating invalid transportation for calcein from internal cavity of P[6] (Fig. 1B). The transport disability supported the fact that the transmembrane transportation should be attributed to native internal voids of P[6] and ruled out the carpet-like disruption or barrel stave mechanism.29In order to demonstrate the transportation activity of the internal cavity directly, the guest molecules were utilized to block the cavity and then disable channeling activity. The previous research showed that the trans form of an azobenzene-containing guest 3 could bind with P[6] forming 1 : 1 host–guest complex.21 The reported host–guest binding affinity may realize an ON–OFF switch in theory. We prepared the trans-3@P[6] complex as previously reported and measured its proton transport activity by HPTS assay.21 As shown in Fig. 2, trans-3@P[6] shows very low ionophoric activity (≤18%) compared with P[6] alone (90%), indicating a successful channel blockage by trans-3 and forming an ON–OFF type channel switch. These significantly reducing fluorescence results suggest that the internal cavity of P[6] plays a critical role in the transport of ions and also provide a coherent evidence supporting that the channeling process is mediated through the P[6] cavity rather than the barrel stave or carpet-like rupture.Open in a separate windowFig. 2(A) Normalized HPTS fluorescence traces as a function of time in the presence of P[6], trans-3@P[6], cis-3@P[6], trans-3 and cis-3 with concentration of 10 μM. (B) Current profiles under +2 V during 16 successive repeat experiments after addition of P[6], trans-3@P[6], cis-3@P[6], trans-3 and cis-3.Next, we demonstrated that the guest molecules neither rupture bilayer membrane nor act as transport channels. As shown in Fig. 2, neither trans-3 nor cis-3 displays transportation efficiency, reaching only up to 10% of the maximal which is almost comparable to blank experiment. Conductance researches of the guest 3 on planar lipid bilayer showed repeatable and feeble current intensities upon addition of trans-3 or cis-3, which demonstrated the invalid transportation and no ruption behavior to membrane.Finally, we investigated further ON–OFF–ON type switch based on photoisomerization of guest 3 from the trans to cis conformation. The previous report has demonstrated that the self-assembly trans-3@P[6] complex could be converted into cis-3@P[6] complex under irradiation of UV light. The binding affinity of cis-3@P[6] significantly decreased to (2.64 ± 0.29) × 102 M−1, which is as low as about 1/8 of trans-3@P[6] ((2.22 ± 0.34) × 103 M−1).21 The cis-3@P[6] complex was constructed and then added into HPTS entrapped-LUVs suspension. As expected, we observed 63% fluorescence intensity increasing which rebounded to 70% transportation performance of P[6] channel (90%). The results demonstrate that cis-3 partially reopened P[6] channel. The diameter of cis-3 is about 0.80 nm which is bigger than the internal cavity of P[6] channel leading to the formation of unthreaded host–guest complex, cis-3@P[6]. The cis-3 was only bound by a rim of P[6], while the rest of cis-3 was outside the cavity.21 In order to eliminate interference, the HPTS assay was constructed using cis-3 or trans-3, only slightly fluorescence increasing was observed which was close to the blank experiment which indicating neither cis-3 nor trans-3 alone affects transportation activity. These results show that P[6] can act as an excellent transmembrane channel, and trans-3 is able to shut down the P[6] channel through host–guest complexation. Then, cis-3 could reopen the blocked P[6] channel due to the decreasing affinity after trans–cis photoisomerization of guest 3, thereby achieving ON–OFF–ON channel switch.In order to achieve further supporting evidence for channelling switches, the conductance examinations were utilized to provide current recordings for ion transportation on planar lipid bilayer.15 At first, the addition of P[6] triggered a significant increase up to 150 pA in the current recordings under applied voltage of 2 V during 16 successive repeat experiments, indicating successful ion transportation through P[6] channel. Then, trans-3@P[6] complex hardly affected current profiles, suggesting P[6] channel was blocked by trans-3 thus obtaining ON–OFF type channel switch. Finally, cis-3@P[6] was introduced to investigate the channeling activity under identical experimental conditions retrieving 90 pA current flows, accounting for 60% of the highest current. Trans-3 or cis-3 alone hardly showed any current which was consistent with fluorescence results. The almost maintaining constant conductance profiles likely to confirm the formation of “single-molecule ligand-gating switch”. Further conductance investigation supplied straightforward evidence to verify the formation of reversible “single-molecule ligand-gating switch”. The current profiles were recorded as a function of time in Fig. 3. In fact, the current flows significantly increased to 150–170 pA after adding P[6] to drive the transmembrane channel formation in planar lipid bilayer and then decreased to 15–25 pA which almost close to planar lipid bilayer alone after further addition of trans-3 to form trans-3@P[6] complex. And then, the current flow enhanced to 90–100 pA after irradiation of UV light, mainly due to the trans-3@P[6] complex undergo trans–cis conversion upon irradiation with UV light at 365 nm for 3 min. Finally, the current flow reduced to 20–30 pA after irradiation of visible light at 435 nm for 3 min. This reversible single-molecule ligand-gating switch could be operated over three times (Fig. S5†). The conductance investigation clearly demonstrated that opening/blocking transition of P[6] channel could be controlled reversibly by a “single-molecule ligand-gating switch”.Open in a separate windowFig. 3Conductance profiles at an applied voltage of +2 V at the lipid bilayer membrane as blank experiment (A), and then adding P[6] in HEPES buffer (10 mM HEPES, 100 mM NaCl, and pH 7.0) (B) before and (C) after addition of trans-3. Then, UV light (D) and visible light (E) irradiation was internally introduced to trigger photoisomerization of 3 between trans and cis conformation. Schematic drawing of a reversible photoresponsive channel switches are displayed on the right side. Proton (blue) channels of P[6] (green) were blocked by trans-3 (red) and reopened after addition of UV light irradiation (365 nm) via photoisomerization of 3 from trans to cis, then P[6] channel was blocked again after visible light irradiation (435 nm) which trigger conformation change from cis-3 to trans-3.In summary, we constructed an innovative reversible pseudo-single-ligand-gated ion transportation switch of ON–OFF–ON type using P[6] as an efficient channel and a photoresponsive azobenzene (guest 3) as the ligand. Firstly, the open internal cavity of P[6] channel could be blocked by trans-3 through host–guest complexation, thereby achieving ON–OFF type switch. Then, the switch could realize the channeling state from OFF to ON and then back to OFF state based on photoisomerization of guest 3, thus obtaining a reversible ON–OFF–ON type switch. Moreover, the “single-molecule ligand-gating switch” could realize multiple recurring applications. Together, “cavitand-channelling”–“photoisomer-blocking–reopening–reblocking” suggests the formation of reversible pseudo-single-ligand-gated ion transportation switch of ON–OFF–ON type. The reversible channelling switch will have a broad application in living organic and pharmaceutical field such as controlling drug release. 相似文献
18.
Jovana Jaki Aleksandra Mitrovi Zorana Toki Vujoevi Milo Mil
i Veselin Maslak 《RSC advances》2021,11(47):29426
In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C60 sphere. Generally, cyclopropanated fullerene derivatives are obtained by the standard Bingel–Hirsch procedure. Herein, omitting the iodine from the reaction mixture and adding TEMPO afforded dihydrofuran fused C60 fullerene derivatives. The mechanism of the reaction shifted from nucleophilic aliphatic substitution to oxidative [3 + 2] cycloaddition via fullerenyl cations as an intermediate. This mechanism is proposed based on a series of control experiments with radical scavengers. Therefore, dihydrofuran-fused C60 derivatives were selectively obtained in good yields and their structures were established based on UV-Vis, IR, NMR spectroscopy and mass spectrometry. The electrochemical properties of the synthesized compounds were investigated by cyclic voltammetry. DFT calculations were performed in order to investigate the difference in stability, electronic properties and π-electron delocalization between methano and furano fullerenes.In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C60 sphere. 相似文献
19.
In this paper, a simple and practical synthesis of benzo[e]benzo[4,5]imidazo[1,2-c][1,3]thiazin-6-imine tetracyclic heterocycles via a CuI nanoparticle-catalyzed intramolecular C(sp2)–S coupling reaction is presented. This strategy provides a straightforward method for synthesizing analogs of the anti-HIV drug 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182). The reaction rate and yield were increased by employing CuI nanoparticles.We proposed a practical synthesis of analogs of the anti-HIV drug 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine via a CuI nanoparticle-catalyzed intramolecular C(sp2)–S coupling reaction. 相似文献
20.
Gangireddy Sujeevan Reddy Kazi Amirul Hossain Jetta Sandeep Kumar B. Thirupataiah Rebecca Kristina Edwin Varadaraj Bhat Giliyaru Raghu Chandrashekhar Hariharapura G. Gautham Shenoy Parimal Misra Manojit Pal 《RSC advances》2019,10(1):289
A series of novel isatin–indole derivatives has been designed as potential inhibitors of chorismate mutase (CM) that is known to be present in bacteria, fungi and higher plants but not in human. The design was supported by in silico docking studies that predicted strong interactions of these molecules with CM. The target compounds were synthesized via the one-pot coupling/cyclization method involving the reaction of an isatin based terminal alkyne with 2-iodosulfanilides under Pd–Cu catalysis. A number of isatin–indole derivatives were prepared using this method. A side product e.g. 2-indolylmethylamino benzoate ester derivative was obtained as a result of isatin ring opening (ethanolysis) of products in certain cases. Additionally, regioselective reduction of selected compounds afforded the corresponding C-3 hydroxy derivatives. All isatin–indole derivatives showed good to high inhibition of CM in vitro among which two compounds (3e and 3f) showed inhibition at nanomolar concentration.Design, synthesis and evaluation of isatin–indole derivatives were undertaken to identify potent inhibitors of chorismate mutase. 相似文献