Publications by authors named "Haibing He"

173 Publications

Studies on the Influence of High-Shear Granulation Process on the Compressibility of Microcrystalline Cellulose.

Int J Pharm 2022 Aug 2:122075. Epub 2022 Aug 2.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

Microcrystalline cellulose (MCC) is a diluent for oral solid dosage forms. The wet granulation process was selected to prepare losartan potassium tablets using MCC as a model for a predictive study. It was found that the hardness of the tablets could not satisfy the quality standards. In this study, the effect of the high-shear granulation process on the compressibility of MCC was characterized by plotting the compression characteristics curve, as well as the mechanism of the effect from the perspectives of mechanical properties, powder properties. The solid-state properties were also analyzed. Combined with the Heckel equation, the Ryshkewitch-Duckworth equation, the energy method, PXRD, SEM, and other evaluation methods, the results suggest that the high-shear granulation process reduced the compressibility of MCC, which may be caused by the reduced plastic deformation capacity of MCC and the change of the particle morphology structure. The method applied in this study can also be applied to other excipients, which is an important guideline for solving possible problems and process selections during the preparation stage of solid formulations.
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http://dx.doi.org/10.1016/j.ijpharm.2022.122075DOI Listing
August 2022

Evaluation of Emulsifying Ability of Phospholipids by Langmuir Monolayers and Stability of High Oil Ratio O/W Emulsions.

AAPS PharmSciTech 2022 Jul 28;23(6):208. Epub 2022 Jul 28.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, People's Republic of China.

High oil ratio fat emulsion injections are prone to poor emulsification, rapid creaming, and other quality problems; therefore, the selection of emulsifiers with high emulsifying ability is crucial for the production of fat emulsions. The existing methods used to evaluate the emulsifying ability of emulsifier are to evaluate the emulsifying ability from the emulsifier itself. In the study, Langmuir monolayer selected the most miscible phospholipid with oil phase from the alternative three phospholipids by studying the molecular interaction between oil phase and phospholipid at the air/water interface. The miscibility and thermodynamic stability analyses of the different oil phase/phospholipid mixed monolayers were performed, and the data from [Formula: see text] and [Formula: see text] concluded that all three oil phases had the strongest molecular interaction with E80 and the best miscibility. The emulsions were then prepared and analyzed by the results of particle size, ζ-potential, and stability of the emulsions, where the surface free energy in the stability test echoed the results reflected by the [Formula: see text] values in the thermodynamic stability test. These results indicate that Langmuir monolayers can be used to study the interaction between oil phase and emulsifier, thus providing new ideas for evaluating the emulsifying ability of phospholipids.
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http://dx.doi.org/10.1208/s12249-022-02325-6DOI Listing
July 2022

Construction and Evaluation of Traceable rhES-QDs-M-MS Protein Delivery System: Sustained-Release Properties, Targeted Effect, and Antitumor Activity.

AAPS PharmSciTech 2022 Jul 28;23(6):207. Epub 2022 Jul 28.

Department of Pharmaceutics, College of Pharmacy, Shenyang pharmaceutical university, Shenyang, 110016, People's Republic of China.

Recombinant human endostatin (rhES) is a protein drug with poor stability and short in vivo circulation time. The present study was therefore aimed at developing sustained-release lung targeted microspheres drug delivery system and evaluating its targeting efficiency using in vivo imaging techniques with quantum dots (QDs) as the imaging material. The oil-soluble QDs were coated with amphiphilic polymers to obtain a polymer-quantum dots micelle (QDs-M) with the potential to stably disperse in water. The rhES and QDs-M were combined using covalent bonds. The rhES-QDs-M microspheres (rhES-QDs-M-MS) were prepared using electrostatic spray technology and also evaluated via in vivo imaging techniques. The pharmacodynamics was further studied in mice. The rhES-QDs-M-MS (4-8 μm) were stable in an aqueous medium with good optical properties. The in vitro studies showed that the rhES-QDs-M-MS had sustained release which was maintained for at least 15 days (cumulative release >80%) without any burst release. The rhES-QDs-M-MS had a very high safety profile and also effectively inhibited the in vitro proliferation of human umbilical vein endothelial cells by about 70%. The pharmacokinetic results showed that the rhES could still be detected at 72 h in the experimental group which meant that the rhES-QDs-M-MS had a significant sustained-release effect. The rhES-QDs-M-MS had a better lung targeting effect and higher antitumor activity compared with the rhES. The traceable rhES-QDs-M-MS served as a promising drug delivery system for the poorly stable rhES proteins and significantly increased its lung-targeted effect, sustained-release properties, and antitumor activities.
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http://dx.doi.org/10.1208/s12249-022-02326-5DOI Listing
July 2022

The effect of granules characters on mechanical properties of press-coated tablets: A comparative study.

Int J Pharm 2022 Jul 9;624:121986. Epub 2022 Jul 9.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, People's Republic of China. Electronic address:

The aim of this study was to investigate the correlation between critical granules characters (including particle size, surface roughness, and apparent porosity) and mechanical properties of press-coated tablets. Granules of a model formulation were prepared through Roll Compaction Granulation (RCG), High Shear Granulation (HSG), and Fluidized Bed Granulation (FBG) to prepare granules with different surface roughness and apparent porosity. The surface roughness and porosity of granules had a significantly greater effect on mechanical properties than the particle size of granules. Whether for brittle or plastic materials, FBG granules with the roughest surface and the greatest apparent porosity exhibited the best compression properties. The elastic recovery test, the interlayer adhesion forces study, the break pattern test, and the X-ray microcomputed tomography investigation suggested that granules with great apparent porosity and rough surfaces could contribute to the production of stable press-coated structures. Moreover, for press-coated tablets prepared using granules, the proper granules in the coat layer could eliminate the side effect of the rigid core on the mechanical strength. The above understandings will be conducive to the selection of compatible and appropriate granules characters, which can enhance mechanical properties and extend the application of press-coated tablets.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121986DOI Listing
July 2022

Preparation, characterization of clonidine hydrochloride resinates and investigation of the kinetics and thermodynamics of the ion exchange process.

Pak J Pharm Sci 2022 May;35(3):721-729

Jiangsu haizhihong biomedical Co., Ltd, Nantongm P.R. China.

Clonidine Hydrochloride (CH) resinates were prepared by plating solution with strong acid cationic-exchange resin as the carrier. The drug resinate's combination mode was characterized by SEM, DSC and X-ray diffraction. The reaction at different temperatures and the influence of different ion exchange resins on the ion exchange process were studied, The kinetics and thermodynamics of ion exchange resins under different temperatures were studied. The In vitro drug liberate from the drug-resinates was investigated in different mediums. The study proved that the combination of CH and resin was not a simple physical mixture but ionic bonded. With the increase of temperature and ion exchange and Amberlite⌖IRP69 had a higher affinity for ionic drugs. The results of In vitro release experiment showed that temperature, medium volume, stirring speed, the ionic strength and type. The In vitro release of CH resin was fitted with Viswanathan equation, it conformed to the process of particle diffusion. Also, the results showed that further coating of CH resin is necessary to achieve a significant continued release effect.
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May 2022

The effects of intermolecular interactions on the stability and in vitro drug release of daunorubicin/cytarabine co-loaded liposome.

Colloids Surf B Biointerfaces 2022 Jun 28;217:112673. Epub 2022 Jun 28.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China. Electronic address:

Various studies were performed on the intermolecular interactions of daunorubicin (DNR) and cytarabine (Ara-C) co-loaded liposome to predict and elucidate its stability and in vitro drug release behavior. Langmuir monolayer and spectroscopy studies showed interactions between its components. The Langmuir monolayer study and blank liposomes stability study illustrated that interactions between lipids could affect their stability, and the DSPC/DSPG/Chol (7/2/1, mol%) mixed system tended to be thermodynamically and physicochemically stable. The interactions between daunorubicin and copper ions were then investigated by ultraviolet-visible (UV-vis) electronic absorption spectroscopy and circular dichroism (CD) spectroscopy, which revealed that the DNR-Cu complex was composed of daunorubicin and copper ions at a molar ratio of 1:1 or 1:2, and its solubility was related to the acidity of the solution. In vitro release experiment of liposomes with different copper gluconate contents illustrated that the interactions between drugs and copper ions were conducive to the retention and synergetic release of drugs. The stability and release studies of the DSPC/DSPG/Chol (7/2/1, mol%) co-loaded liposome illustrated that it had good storage and plasma stability, and the release behaviors of drugs were pH-related, i.e., drugs could be released faster under acidic condition. These studies indicated that intermolecular interactions could affect the stability and release behavior of the liposome, and a certain ratio of components could be conducive to its stability and synergistic release of drugs.
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http://dx.doi.org/10.1016/j.colsurfb.2022.112673DOI Listing
June 2022

Inflammation-targeted sialic acid-dexamethasone conjugates for reducing the side effects of glucocorticoids.

Int J Pharm 2022 Jun 8;622:121900. Epub 2022 Jun 8.

Department of Pharmaceutics, Shenyang Pharmaceutical University, Wenhua Road No.103, Shenyang, China.

As a potent glucocorticoid drug (GCs), Dexamethasone (Dex) is widely used clinically for the treatment of inflammatory diseases. However, such side effects as Cushing's syndrome and osteoporosis caused severe distress to patients. Herein, a sialic acid (SA)-modified dexamethasone conjugate (Dex-SA) was synthesized successfully to reduce side effects by targeting inflammatory diseases. The solubility of Dex-SA in water reached 58 times that of Dex, which meets the need for intravenous administration. The excellent stability of Dex-SA in plasma also laid a foundation for targeting disease sites. According to cellular uptake and biodistribution experiments, Dex-SA was more readily to be taken up by inflammatory cells and accumulated in diseased kidneys compared to Dex, which is attributed to the interaction of SA with E-selectin receptors overexpressed on the surface of inflammatory vascular endothelial cells. Besides, the pharmacodynamics studies of acute kidney injury showed that Dex-SA and Dex could produce comparable therapeutic effects. More importantly, Dex-SA was found to significantly reduce Dex-related side effects, as measured by blood glucose, red blood cells and immune cells, etc. At last, molecular docking results were obtained to confirm that Dex-SA could enter the cells by binding specifically with the E-selectin receptor, for combination with glucocorticoid receptors in the cytoplasm to exert pharmacological effects. Our study is expected to contribute a new strategy to the safe and effective targeting treatment of inflammatory diseases.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121900DOI Listing
June 2022

Chitosan-Coated Liposomes: The Strategy to Reduce Intestinal Toxicity and Improve Bioavailability of Oral Vinorelbine.

AAPS PharmSciTech 2022 Jun 10;23(5):163. Epub 2022 Jun 10.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, People's Republic of China.

In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the risk of phlebitis is avoided with oral administration, oral vinorelbine is still not a highly patient-compliant route due to the severe gastrointestinal toxicity. Vinorelbine-loaded liposomes with high encapsulation efficiency and suitable particle size were prepared using the ammonium sulfate gradient method. Chitosan-coated liposomes showed the slowest in vitro release compared to uncoated liposomes and vinorelbine solution. No damage was observed in the intestinal epithelial cells of mice orally administered with coated vinorelbine liposomes due to the low presence of the free drug in the gastrointestinal tract and the LD was increased from 129.83 to 182.25 mg/kg compared to oral vinorelbine solution. In addition, the positive surface potential of chitosan-coating endowed liposomes with mucosal adhesive function, delaying the time to reach the peak plasma concentration of vinorelbine from 1 to 4 h after administration. And bioavailability was increased to 2.1-fold compared to vinorelbine solution. In short, a new strategy to address the severe gastrointestinal side effects of oral vinorelbine has been developed.
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http://dx.doi.org/10.1208/s12249-022-02308-7DOI Listing
June 2022

Thermodynamic stability of cisplatin-loaded polymeric micelles and the phenotypic switching of the tumor-associated macrophages induced by combination of cisplatin-loaded micelles and Anti-PD-L1 antibody.

Int J Pharm 2022 Jun 30;622:121860. Epub 2022 May 30.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China. Electronic address:

Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121860DOI Listing
June 2022

Sphingomyelin-based PEGylation Cu (DDC) liposomes prepared via the dual function of Cu for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects.

Int J Pharm 2022 Jun 2;621:121788. Epub 2022 May 2.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110116, China.

The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu (DDC), the complex of diethyldithiocarbamate (DDC, DSF metabolite) and Cu, have been proven as the vital active component on cancer, which have aroused the attention of researchers from DSF to Cu (DDC). However, the poor water solubility of Cu (DDC) increase more difficulties to the treatment and in-depth investigations of Cu (DDC). In this study, sphingomyelin (SM)-based PEGylated liposomes (SM/Chol/DSPE-mPEG (55:40:5, mole%)) were produced as the carriers for Cu (DDC) delivery to enhance the water solubility. DDC was added to Cu-containing liposomes with a higher encapsulation efficiency of more than 90%, and it reacted with Cu to synthesize Cu (DDC). Due to the high phase transition temperature of SM and strong intermolecular hydrogen bonds with cholesterol, SM-based liposomes would be conducive to enhancing the stability of Cu (DDC) and preventing drug leakage during delivery. As proven by pharmacokinetic studies, loading Cu (DDC) into liposomes improve bioavailability, and the area under the curve (AUC) and the mean elimination half-life (t) increased 1.9-time and 1.3-time to those of free Cu (DDC), respectively. Furthermore, the anticancer effect of Cu (DDC) was enhanced by the liposomal encapsulation, thus resulting in remarkable cell apoptosis in vitro and a tumor-inhibiting rate of 77.88% in vivo. Thus, it was concluded that Cu (DDC) liposomes could be promising in cancer treatment.
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http://dx.doi.org/10.1016/j.ijpharm.2022.121788DOI Listing
June 2022

Preclinical evaluations of Norcantharidin liposome and emulsion hybrid delivery system with improved encapsulation efficiency and enhanced antitumor activity.

Expert Opin Drug Deliv 2022 04 11;19(4):451-464. Epub 2022 Apr 11.

Department of Oncology, Shengjing Hospital of China Medical University, Shenyang,China.

Background: Norcantharidin (NCTD) has a certain degree of hydrophilicity and poor lipophilicity, and has some side-effects, including short t, vascular irritation, cardiotoxicity, and nephrotoxicity, which bring difficulties for formulation research. In this study, we aim to develop a novel nanocarrier to improve encapsulation efficiency, increase sterilization stability, and enhance antitumor activity.

Methods: Phospholipid complexes methods were used for increasing the lipophilicity of norcantharidin (NCTD), then NCTD phospholipid complexes were not only loaded in the oil phase and oil-water interface surface, but also encapsulated in phospholipid bilayers to obtain NCTD liposome-emulsion hybrid (NLEH) delivery system. The cytotoxicity and apoptosis, tissue distribution, tumor penetration, heterotopic, and orthotopic antitumor studies were conducted to evaluate therapeutic effect.

Results: NLEH exhibited an improved encapsulation efficiency (89.3%) and a better sterilization stability, compared to NCTD liposomes and NCTD emulsions. NLEH can achieve a better antitumor activity by promoting absorption (1.93-fold), prolonging blood circulation (2.08-fold), enhancing tumor-targeting accumulation (1.19 times), improving tumor penetration, and increasing antitumor immunity.

Conclusions: The liposome-emulsion hybrid (LEH) delivery system was potential carrier for NCTD delivery, and LEH could open opportunities for delivery of poorly soluble anticancer drugs, especially drugs that are more hydrophilicity than lipophilicity.
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http://dx.doi.org/10.1080/17425247.2022.2063834DOI Listing
April 2022

Total synthesis of streptovertidione and bioinspired transformation to streptovertidine A and formicapyridine A.

Chem Commun (Camb) 2022 Mar 29;58(26):4239-4242. Epub 2022 Mar 29.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China.

We report herein a concise total synthesis of streptovertidione, and its transformation to streptovertidine A and formicapyridine A through a bioinspired pyridination. This strategy features: (1) a one-pot Ti(O-Pr)-mediated photoenolization/Diels-Alder (PEDA) reaction/oxidative aromatization sequence for the construction of -dimethyl-anthracenone, a naturally occurring antibiotic pharmacophore; (2) a late-stage pyridination based on the biosynthetic hypothesis. This efficient route supports the preparation of other formicapyridines and derivatives.
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http://dx.doi.org/10.1039/d2cc00947aDOI Listing
March 2022

Improved Core Viscosity Achieved by PDLLACo-Incorporation Promoted Drug Loading and Stability of mPEG-b-PDLLA Micelles.

Pharm Res 2022 Feb 3;39(2):369-379. Epub 2022 Feb 3.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, People's Republic of China.

Purpose: This study aims to investigate the effect of poly(D, L-lactic acid) (PDLLA) incorporation on the drug loading and stability of poly(ethylene glycol)-block-poly(D, L-lactide) (mPEG-b-PDLLA) micelles. In addition, a suitable lyophilization protector was screened for this micelle to obtain favorable lyophilized products.

Methods: The incorporation ratios of PDLLA were screened based on the particle size and drug loading. The dynamic stability, core viscosity, drug release, stability in albumin, and in vivo pharmacokinetic characteristics of PDLLA incorporated micelles were compared with the original micelles. In addition, the particle size variation was used as an indicator to screen the most suitable lyophilization protectant for the micelles. DSC, FTIR, XRD were used to illustrate the mechanism of the lyophilized protectants.

Results: After the incorporation of 5 wt% PDLLA, the maximum loading of mPEG-b-PDLLA micelles for TM-2 was increased from 26 wt% to 32 wt%, and the in vivo half-life was increased by 2.25-fold. Various stability of micelles was improved. Also, the micelles with hydroxypropyl-β-cyclodextrin (HP-β-CD) as lyophilization protectants had minimal variation in particle size.

Conclusions: PDLLA incorporation can be employed as a strategy to increase the stability of mPEG-b-PDLLA micelles, which can be attributed to the viscosity building effect. HP-β-CD can be used as an effective lyophilization protectant since mPEG and HP-β-CD form the pseudopolyrotaxanesque inclusion complexes.
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http://dx.doi.org/10.1007/s11095-022-03174-5DOI Listing
February 2022

Relationship Between the Vascular Bundle Structure of Panicle Branches and the Filling of Inferior Spikelets in Large-Panicle Japonica Rice.

Front Plant Sci 2021 15;12:774565. Epub 2021 Dec 15.

College of Agronomy, Anhui Agricultural University, Hefei, China.

The vascular bundles of rice panicles serve to connect the source and the sink, as well as serving as a channel for the transportation of materials. In this study, two homozygous japonica rice strains were used as materials. The vascular bundle structures of the branches in different positions within a rice panicle were observed, and their cross-sectional areas were calculated. In addition, the ultrastructure of the central large vascular bundle (LVB) phloem in the rachillae of superior spikelets (SS) and inferior spikelets (IS) was observed during the grain filling period. Moreover, the soluble sugar and protein contents of the SS and IS rachillae were also measured to study whether the differences in the structure of vascular bundles of the branches were related to the plumpness of grain at different positions. The results showed that vascular bundle cross-sectional areas of the basal primary branches were greater than those in the upper primary branches. Moreover, there was little difference in the areas of vascular bundles between the basal secondary branches and upper secondary branches. However, the vascular bundle areas of the IS rachillae were lower than those in the SS rachillae. Therefore, we believe that the poor vascular tissue channel of the IS rachillae could be the limiting factor in IS plumpness. The results also showed that a similar time course in the degradation pattern of some organelles of the sieve elements and companion cells in central LVB was observed in the SS rachillae and IS rachillae during the grain filling period. Compared with the IS rachillae, more abundant mitochondria and plasmodesmata were found in the companion cells of SS rachillae at the beginning of the filling stage, while no significant differences between SS and IS rachillae were identified at the middle and late filling stages, which implies that the SS rachillae were relatively more effective at transportation compared with the IS rachillae at the initial filling stage. Therefore, the undeveloped vascular bundles of the IS rachillae and their poor physiology and lack of ability to transport at the initial filling stages could be the limiting factor in IS plumpness.
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http://dx.doi.org/10.3389/fpls.2021.774565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714962PMC
December 2021

Preparation and Evaluation of rhINF-α-2b Sodium Hyaluronate Cross-Linked Porous Microspheres: Characterization, Sustained-Release Properties, and Antitumor Activity.

AAPS PharmSciTech 2021 Dec 20;23(1):31. Epub 2021 Dec 20.

Department of pharmaceutics, College of pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, P.R. China.

Recombinant human interferon α-2b (rhINF-α-2b), like most proteins, has several shortcomings such as relatively short half-life, low therapeutic index, high circulating drug fluctuations, and rapid degradation which could hinder its effective delivery. Novel electrostatic spray and ion exchange drug-loading techniques were combined to formulate rhINF-α-2b sodium hyaluronate cross-linked porous sustained-release microspheres (rhINF-α-2b-SHCPM), a protein delivery system. The different properties of rhINF-α-2b-SHCPM including the physicochemical nature, in vitro release behavior, and antitumor activity were evaluated. The loading rate (10.31 ± 0.94%) and encapsulation efficiency (89.09 ± 2.37%) of rhINF-α-2b-SHCPM produced acceptable values. The in vitro cumulative release rate of rhINF-α-2b-SHCPM within 24 h was also 86.26 ± 2.11% with a much better sustained release effect. Thus, the half-life (10.763 h) and retention time (14.067 h) of rhIFNα-2b-SHCPM were significantly prolonged with enhanced bioavailability (43,198.387 ng/L*h) and decreased peak concentration (15,266.4 ngL) compared with the free rhIFNα-2b protein (0.912 h, 0.952 h, 34,749.048 ng/L*h, and 48,870.2 ngL, respectively). The in vitro anti-proliferative activity and in vivo tumor inhibitory rate of rhIFNα-2b-SHCPM also increased by 90 and 55.86%, respectively, compared with the free rhIFNα-2b solution. The findings significantly supported a well-developed protein delivery system with improved sustained release, acceptable bioavailability, and increased antitumor activities. Graphical Abstract.
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http://dx.doi.org/10.1208/s12249-021-02178-5DOI Listing
December 2021

Co-delivery of gemcitabine and cisplatin via Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) micelle to improve the in vivo stability and antitumor effect.

Pharm Res 2021 Dec 10;38(12):2091-2108. Epub 2021 Dec 10.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People's Republic of China.

Purpose: The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect.

Methods: A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles ([email protected] micelles).

Results: Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h ([email protected]), 5.463 h and 12.540 h ([email protected]) compared with [email protected]DDP solutions (T = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that [email protected] was more toxic to kidneys and marrow compared with [email protected] micelles.

Conclusions: By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Scheme. Schematic of [email protected] micelles' formation and action process.
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http://dx.doi.org/10.1007/s11095-021-03139-0DOI Listing
December 2021

Two-step fabricating micelle-like nanoparticles of cisplatin with the 'real' long circulation and high bioavailability for cancer therapy.

Colloids Surf B Biointerfaces 2022 Feb 20;210:112225. Epub 2021 Nov 20.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.

Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy.
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http://dx.doi.org/10.1016/j.colsurfb.2021.112225DOI Listing
February 2022

Fabrication and evaluation for the novel ranitidine hydrochloride resinates and calculation of the kinetics and thermodynamics parameter for the ion exchange process.

Pak J Pharm Sci 2021 Sep;34(5):1715-1722

School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, PR China/International Healthcare Innovation Institute (Jiangmen), Jiangmen, PR China.

Ranitidine hydrochloride (RH) resinates were prepared by bath method using a highly acidic cation-exchange resin as the carrier. The drug-resinates combination pattern was characterized by DSC and X-ray diffraction. The influences of the types of the ion-exchange resin, initial RH concentration and the reaction temperature on the process of ion exchange were investigated. Three empirical kinetics models and thermodynamics equations were studied to the ion exchange process under different temperatures. The results showed that RH combined with ion-exchange resin not simple physical mixture but by ion bond, and the rate of ion exchange increased on increasing the initial drug concentration and reducing the temperature the resin. The in vitro drug release test showed that the release process was affected by the kind of countra-ion, ionic strength and temperature. Thermodynamics results showed that the ion exchange reaction between RH and cation-exchange resin was exothermic (ΔH <0), and the drug release process could preferably be fitted with the first order equation. In conclusion, RH resinates were prepared by the bath method with strongly acidic cation-exchange (Amberlite® IRP69) with 5 mg/mL RH solution(100mL) stirred at 298K for 1h. Drug release from resinates was fitted with Viswanathan equation, and to achieve obvious sustained-release effect, the RH-resin complex should be further coated with a semipermeable membrane.
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September 2021

Impact of jet pulverization and wet milling techniques on properties of aripiprazole long-acting injection and absorption mechanism research in vivo.

Int J Pharm 2022 Jan 15;612:121300. Epub 2021 Nov 15.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC of 5243.7 μg·L·h and 4818.28 μg·L·h, respectively. Furthermore, no statistically significant differences in C t and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later T after depletion of macrophages and significantly lower C and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.
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http://dx.doi.org/10.1016/j.ijpharm.2021.121300DOI Listing
January 2022

Stable Atropine Loaded Film As a Potential Ocular Delivery System For Treatment Of Myopia.

Pharm Res 2021 Nov 12;38(11):1931-1946. Epub 2021 Nov 12.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Purpose: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia.

Methods: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs.

Result: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia.

Conclusion: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.
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http://dx.doi.org/10.1007/s11095-021-03135-4DOI Listing
November 2021

C-Glycoside metabolism in the gut and in nature: Identification, characterization, structural analyses and distribution of C-C bond-cleaving enzymes.

Nat Commun 2021 11 2;12(1):6294. Epub 2021 Nov 2.

Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.

C-Glycosides, in which a sugar moiety is linked via a carbon-carbon (C-C) bond to a non-sugar moiety (aglycone), are found in our food and medicine. The C-C bond is cleaved by intestinal microbes and the resulting aglycones exert various bioactivities. Although the enzymes responsible for the reactions have been identified, their catalytic mechanisms and the generality of the reactions in nature remain to be explored. Here, we present the identification and structural basis for the activation of xenobiotic C-glycosides by heterocomplex C-deglycosylation enzymes from intestinal and soil bacteria. They are found to be metal-dependent enzymes exhibiting broad substrate specificity toward C-glycosides. X-ray crystallographic and cryo-electron microscopic analyses, as well as structure-based mutagenesis, reveal the structural details of these enzymes and the detailed catalytic mechanisms of their remarkable C-C bond cleavage reactions. Furthermore, bioinformatic and biochemical analyses suggest that the C-deglycosylation enzymes are widely distributed in the gut, soil, and marine bacteria.
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http://dx.doi.org/10.1038/s41467-021-26585-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563793PMC
November 2021

Rod-shaped nintedanib nanocrystals improved oral bioavailability through multiple intestinal absorption pathways.

Eur J Pharm Sci 2022 Jan 20;168:106047. Epub 2021 Oct 20.

Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China.

Nintedanib (BIBF) is a biopharmaceutical classification system II (BCS II) drug that has a good therapeutic effect for the treatment of nonsmall cell lung cancer; however, it shows poor oral bioavailability due to low dissolution and intestinal absorption. This study aims to fabricate rod-shaped nanocrystals to enhance oral bioavailability by improving the dissolution and absorption of BIBF in the intestine. By prescription screening, BIBF nanocrystals (BIBF-NCs) with a particle size of 325.30 ± 1.03 nm and zeta potential of 32.70 ± 1.24 mV were fabricated by an antisolvent precipitation-ultrasound approach with a stabilizer of sodium carboxyl methyl cellulose (CMC-Na). BIBF-NCs exhibited a rod-shaped morphology by transmission electron microscopy (TEM). The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) showed that the crystal form of BIBF in BIBF-NCs was altered. The BIBF-NCs remarkably improved the saturation solubility and dissolution of BIBF compared with BIBF powder. According to the results of in situ single-pass intestinal perfusion (SPIP), BIBF-NCs showed improved absorption and membrane permeability, with K and P values in the jejunum of 0.21 ± 0.01 min and (4.34 ± 0.11) × 10 cm/min, respectively. Further, the K and P values of BIBF-NCs were all reduced significantly after the addition of inhibitors colchicine, chlorpromazine and indomethacin, which demonstrated that BIBF-NCs could be absorbed by endocytosis mediated by caveolae and clathrin and micropinocytosis in the intestine. The cell evaluation results showed that BIBF-NCs could be taken up by macrophages and transported from Caco-2 monolayers. The in vivo pharmacokinetic results showed that the bioavailability of the BIBF-NCs was 2.51-fold higher than that of the BIBF solution (BIBF-Sol) after oral administration with a longer T (4.50 ± 1.00 h vs. 2.60 ± 1.92 h). In summary, rod-shaped BIBF-NCs could significantly improve oral bioavailability through multiple intestinal absorption pathways.
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http://dx.doi.org/10.1016/j.ejps.2021.106047DOI Listing
January 2022

-Selective and Enantioselective Photoenolization/Diels-Alder Reaction.

Org Lett 2021 Oct 22;23(19):7487-7491. Epub 2021 Sep 22.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China.

An unusual -selective photoenolization/Diels-Alder reaction of electron-rich 2-methylbenzaldehydes and dienophiles containing a benzoyl group at its α position was reported herein. The chiral TADDOL-type ligand plays a key role in this process: (1) accelerating the reaction; (2) controlling the enantioselectivity; and (3) improving and tuning the diastereoselectivity of the reaction.
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http://dx.doi.org/10.1021/acs.orglett.1c02719DOI Listing
October 2021

Photosynthetic physiological response of water-saving and drought-resistant rice to severe drought under wetting-drying alternation irrigation.

Physiol Plant 2021 Dec 17;173(4):2191-2206. Epub 2021 Oct 17.

Agricultural College, Anhui Agricultural University, Hefei, Anhui, China.

Water-saving and drought-resistant rice (WDR) is widely grown in central China in recent years. However, studies have not explored the interaction effect of WDR and irrigation regimes on drought-resistance capacities under severe drought at sensitive growth periods. A pot experiment was conducted using a WDR cultivar Hanyou73 (HY73) and traditional high-yielding and drought-sensitive cultivar Huiliangyou 898 (HLY898). Three irrigation regimes, including flooding irrigation (W1), mild wetting-drying alternation irrigation (W2), and severe wetting-drying alternation irrigation (W3), were applied before heading. At heading, severe drought with -50 KPa soil water potential was established for all treatments and cultivars. The findings showed that cultivar HY73 under W2 treatment had the highest yield, 1000-grain yield, filled grain, relative water content, and photosynthesis potential compared with the other combinations. The higher net photosynthetic rate (P ) was attributed to larger mesophyll conductance (g ) in drought for cultivar HY73 under W2 treatment compared with that for cultivar HLY898 and the other water treatments. Enhanced photo-respiration rate may be an important photoprotection mechanism for achieving high P for cultivar HY73 coupled with W2 treatment than for other combinations in drought. The relative expression level of OsPIP1;1 gene was significantly down-regulated during drought in all cultivars and water regimes. But OsPIP1;2, OsPIP2;3, OsTIP2;2, and OsTIP3;1 genes were upregulated to alleviate the significant decrease in g and g under drought. These results suggest that WDR and mild wetting-drying alternation irrigation (W2) have significant interaction effects in improving photosynthetic production potential by maintaining higher g under severe drought.
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http://dx.doi.org/10.1111/ppl.13568DOI Listing
December 2021

High sodium chloride affects BMP-7 and 1α-hydroxylase levels through NCC and CLC-5 in NRK-52E cells.

Ecotoxicol Environ Saf 2021 Dec 13;225:112762. Epub 2021 Sep 13.

The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, PR China; Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou, Guangdong, 510630, PR China. Electronic address:

A diet high in sodium chloride (NaCl) can affect renal function damage and increase urinary calcium excretion, leading to bone loss. in renal tubules, Na-Cl co-transporter (NCC) and chloride channel 5 (CLC-5) are involved in regulating urinary calcium excretion. In addition, some cytokines, such as Bone morphogenetic protein 7 (BMP-7) and 1α-hydroxylase, are synthesized by renal tubules, which target on bone and play important roles on bone metabolism. However, the specific mechanisms between NaCl and these ion channels or cytokines still need investigations from many aspects. This study, in culture normal rat renal tubular epithelial NRK-52E cells, showed that high concentrations of NaCl significantly inhibited the cell viability and increased the cell apoptosis. High concentration of NaCl reduce bone mineral density (BMD), as demonstrated by the significantly increased mRNA and protein levels of NCC and osteopontin (OPN), but decreased the levels of CLC-5, BMP-7, and 1α-hydroxylase. In addition, we found that ovariectomized (OVX) rats on a high-salt diet for 12 weeks had altered levels of these indices in the renal cortices. Moreover, the BMD in fourth and fifth lumbar vertebra (LV4 and 5) and femurs were significantly decreased and bone microstructure was destroyed of these rats. We also demonstrated that high concentration of NaCl enhanced the inhibition of these cytokines which is beneficial to increase BMD, induced by modulating ion channels NCC and CLC-5. In conclusion, our results indicate that high concentration of NaCl reduce BMD by regulating ion channels NCC and CLC-5.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112762DOI Listing
December 2021

Asymmetric polymersomes, from the formation of asymmetric membranes to the application on drug delivery.

J Control Release 2021 10 5;338:422-445. Epub 2021 Sep 5.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China. Electronic address:

Nano drug delivery systems have attracted researchers' growing attention and are gradually emerging into the public views. More and more nano-formulations are being approved for marketing or clinical use, representing the field's booming development. Copolymer self-assembly systems such as micelles, nanoparticles, polymersomes occupy a prominent position in the field of nano-drug delivery carriers. Among them, polymersomes, unlike micelles or nanoparticles, resemble liposomes' structure and possess large internal hollow hydrophilic reservoirs, allowing them to carry hydrophilic drugs. Nevertheless, their insufficient drug loading efficiency and unruly self-assembly morphology have somewhat constrained their applications. Especially for the delivery of biomacromolecule such as peptides, the encapsulation efficiency is always considered to be a formidable obstacle, even if the enormous hydrophilic core would render the polymersomes to have considerable potential in this regard. Reassuringly, the emergence of asymmetric polymersomes holds the prospect of solving this problem. With the development of synthetic technology and a deeper understanding of the self-assembly process, the asymmetric polymersomes which are with different inner and outer shell composition have been gradually recognized by researchers. It has made possible elevated drug loading, more controllable assembly processes and release performance. The internal hydrophilic blocks different from the outer shell could be engineered to have a more remarkable affinity to the cargos or could contain a non-watery aqueous phase to enable the thermodynamically preferred encapsulation of cargos, which would allow for a substantial improvement in drug encapsulation efficiency compared to the conventional approach. In this paper, we aim to deepen the understanding to asymmetric polymersomes and lay the foundation for the development of this field by describing four main elements: the mechanism of their preparation and asymmetric membrane formation process, the characterization of asymmetric membranes, the efficient drug loading, and the special stimulus-responsive release mechanism.
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http://dx.doi.org/10.1016/j.jconrel.2021.09.003DOI Listing
October 2021

Novel injectable progesterone-loaded nanoparticles embedded in SAIB-PLGA in situ depot system for sustained drug release.

Int J Pharm 2021 Sep 18;607:121021. Epub 2021 Aug 18.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) have attracted considerable interest in the medical community as a sustained-release drug delivery system for localized treatment. However, it is currently a grand challenge to simultaneously achieve low-dose drugs, stable and prolonged drug release, and long-term retention circumventing uptake by macrophages. Here, we construct a solvent-exchange in-situ depot system by incorporating progesterone (PRG) loaded PLGA NPs into a sucrose acetate isobutyrate (SAIB) and PLGA matrix for the long term treatment of Assisted Reproductive Technology (ART). The results showed that different solvent and PLGA contents could affect the drug release rate of PRG NPs-SAIB-PLGA in-situ depot system (PSPIDS). When DMSO was used as solvent with the addition of 8% PLGA to the depot, PSPIDS could achieve a constant drug release with no burst for 2 weeks in vitro. After a single intramuscular injection, such PSPIDS showed higher drug concentration and AUC (6773.0 ± 348.8 μg/L·h) over the entire 7-day testing period compared with the commercial multiple-day-dosing intramuscular PRG-oil solution (1914.5 ± 180.7 μg/L·h) in vivo. Importantly, PSPIDS could be administered at a dose of 3.65 mg/kg, which was one fourth of dose required for PRG-oil solution. The results demonstrate that PRG NPs could successfully achieve both reduced administered dosage and burst release, and therefore that PSPIDS is a promising long-acting composite system for hydrophobic drugs.
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http://dx.doi.org/10.1016/j.ijpharm.2021.121021DOI Listing
September 2021

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B.

Chem Sci 2021 Feb 19;12(13):4747-4752. Epub 2021 Feb 19.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University 3663N Zhongshan Road Shanghai 200062 China

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6-7 steps using an easily accessible -cyclohexadienone derivative. The [6,6]-bicyclic decalin B-C ring and the all-carbon quaternary stereocenter at C-6 were prepared a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D-E ring was constructed through a sequence of Ti(Oi-Pr)-promoted photoenolization/Diels-Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.
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http://dx.doi.org/10.1039/d0sc07089kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179641PMC
February 2021

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters an enantioselective photoenolization/Diels-Alder reaction.

Chem Sci 2021 Apr 27;12(21):7575-7582. Epub 2021 Apr 27.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering East China Normal University 3663 North Zhongshan Road Shanghai 200062 China

All-carbon quaternary stereocenters are ubiquitous in natural products and significant in drug molecules. However, construction of all-carbon stereocenters is a challenging project due to their congested chemical environment. And, when vicinal all-carbon quaternary stereocenters are present in one molecule, they will dramatically increase its synthetic challenge. A chiral titanium promoted enantioselective photoenolization/Diels-Alder (PEDA) reaction allows largely stereohindered tetra-substituted dienophiles to interact with highly active photoenolized hydroxy--quinodimethanes, delivering fused or spiro polycyclic rings bearing vicinal all-carbon quaternary centers in excellent enantiomeric excess through one-step operation. This newly developed enantioselective PEDA reaction will inspire other advances in asymmetric excited-state reactions, and could be used in the total synthesis of structurally related complex natural products or drug-like molecules for drug discovery.
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http://dx.doi.org/10.1039/d1sc00883hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171339PMC
April 2021

Asymmetric Total Synthesis of Aglacins A, B, and E.

Angew Chem Int Ed Engl 2021 07 22;60(30):16655-16660. Epub 2021 Jun 22.

Shanghai Key Laboratory of Green Chemistry and Chemical, Processes, School of Chemistry and Molecular Engineering, East China Normal University, China.

An asymmetric photoenolization/Diels-Alder (PEDA) reaction between electron-rich 2-methylbenzaldehydes and unsaturated γ-lactones was developed to directly construct the basic tricyclic core of aryltetralin lactone lignans. This methodology enabled the first asymmetric total synthesis of aglacins A, B, and E and revision of the absolute configuration of these natural lignans. The strategy was also used to prepare the naturally occurring aryldihydronaphthalene-type lignans (-)-7,8-dihydroisojusticidin B and (+)-linoxepin in four and six steps, as well as 27 natural-product-like molecules containing a C8' quaternary center. We believe that the synthetic aglacins and small-molecule library provide new opportunities to carry out the SAR studies of the podophyllotoxin family of natural products.
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http://dx.doi.org/10.1002/anie.202105395DOI Listing
July 2021
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