Zhenmin Mao

NOVEL SYNTHESIS OF 4- OR 6-SUBSTITUTED INDIRUBIN DERIVATIVES

A simple and convenient route for synthesis of a series of 4- or 6-substituted indirubin derivatives by oxidation and subsequent condensation of indoxyl and isatin is described. Acidic reaction conditions are crucial to the condensation of 4-substituted derivatives, whereas for the condensation of 6-substituted derivatives, both acidic and basic conditions work well.

Synthesis, Cytotoxic, and Antibacterial Evaluation of Quinazolinone Derivatives with Substituted Amino Moiety

A series of novel quinazolinone derivatives containing a substituted amino moiety were synthesized, evaluated for their cytotoxic and antibacterial activities. The results of MTT assay showed that all synthesized target compounds 5A – 5O showed potent cytotoxicity against SGC‐7901 (IC50, 0.72 – 1.41 μm). Moreover, the compounds 5D, 5I, and 5K showed better selectivity as compared with positive controls pemetrexed and MTX due to weak cytotoxicity against normal tissue cell line HUVSMC. Among synthesized compounds, the compounds 5E, 5J, 5L, and 5N showed broad‐spectrum cytotoxic activities against at least four cancer cell lines at a micromolar level. The results of antibacteria evaluation revealed that all synthesized compounds showed good to moderate antibacterial activities against Gram‐negative bacteria Escherichia coli. Among them, the MIC values of the compounds 5C, 5F, and 5M were 0.31 μg/mL.

PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations

A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug.

SYNTHESIS OF PYRROLO[2,3-d]PYRIMIDINE ANALOGUES OF THE POTENT ANTITUMOR AGENT N-{4-[3-(2,4-DIAMINO-7H-PYRROLO-[2,3-d]PYRIMIDIN-5-YL)PROPYL]BENZOYL}-L-GLUTAMIC ACID (TNP-351)

Two three-atom-bridged analogues of TNP-351, N-(4-{[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)amino]methyl}-benzoyl)-L-glutamic acid (4) and N-(4-{[(2,4-diamino-7H-pyrrolo[2,3-d]-pyrimidin-5-ylmethyl)amino]methyl}benzoyl)-L-glutamic acid (5) were synthesized as anticancer agents, and their biological activities were evaluated.

Acrylate copolymer: a rate-controlling membrane in the transdermal drug delivery system

Abstract A film-like copolymer composed of 2-hydroxy-3-phenoxypropylacrylate, 4-hydroxybutyl acrylate and cyclohexyl methacrylate was synthesized and exploited as a rate-controlling membrane in the transdermal drug delivery systems (TDDs). A series of acrylate copolymers with different formulations were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry and tensile strength, and then evaluated by clonidine hydrochloride transporting through the films. It was found that the formulation M2 composed of three monomers at a ratio of 4:4:2 (w/w/w) showed excellent mechanical and permeation properties. The optimal formulation M2 was further characterized by scanning electron microscopy, contact angles and swelling ratio, and then the permeation behaviors of five different physicochemical drugs transporting through the M2 were evaluated. The results showed that the permeation behaviors were influenced by many factors including the thickness of the membrane, the physicochemical properties of the drugs, the dose of the drugs and the interactions between the drugs and the membrane. This type of copolymer membrane might open new applications in the field of TDDs.

Synthesis and Biological Evaluation of 3-Substituted-4-(4-methylthio phenyl)-1HPyrrole Derivatives as Potential Anticancer Agents

A novel series of 3-substituted-4-(4-methylthio phenyl)-1H-pyrrole derivatives were synthesized via Van Leusen pyrrole synthesis. The in vitro anticancer activity against a panel of 16 cancer cell lines and 2 normal cell lines was investigated by MTT assay. It was found that some of the pyrrole compounds showed similar antiproliferative activity against cancer cells compared with Paclitaxel, but little impact on normal cell lines, which indicated that the novel pyrrole derivatives could be used as potential anticancer candidates for possessing both selectivity and good therapeutic efficacy. Structure-activity relationship analysis found that 3-phenylacetyl-4- (4-methylthio phenyl)-1H-pyrrole derivatives displayed the most strong anticancer activity, among which [4-(4-methylthio phenyl)-1Hpyrrol- 3-yl] (4-methoxy phenyl) methanone (3j) was employed to investigate the effect of these pyrrole analogues on cell cycle by propidium iodide (PI) staining on cell flow cytometry. Cell necrotic effect of 10.0 µM 3j against MGC80-3 cells were also observed under fluorescence microscope and transmission electron microscope by ultrathin sections observation.

SYNTHESIS OF PYRROLO[2,3-d]PYRIMIDINE ANALOGUES: PYRIDINE RING ANALOGUES OF PEMETREXED

Two analogues of pemetrexed with its phenyl ring replaced with pyridine ring as novel anticancer agents were synthesized. Preliminary in vitro evaluation indicated that replacement of the phenyl moiety of pemetrexed by the pyridine ring with the 6-5 bicyclic ring system showed low cytotoxicity, that departs from the findings with antifolates bearing 6-6 bicyclic ring system.

Novel Synthesis of Aza-phthalimidine Hydroxylactams

Abstract A novel and convenient synthetic route for preparing aza-phthalimidine hydroxylactams (5a–j) by N-bromosuccinimide (NBS) was developed. This method involved the substitution reactions of substrates (3a–j) with NBS via unstable intermediate bromides (4a–j) rapidly hydrolyzed into hydroxyl products in the course of the workup process.

Synthesis, characterization and molecular dynamics simulation of the polyacrylates membranes

Abstract The aims of this paper are to investigate the inherent relationship between the structures of the polyacrylates and release behaviors as drug carriers in the transdermal drug delivery systems. Three model polyacrylates compounds were synthesized by radical polymerization. Three polymer materials were characterized by Fourier transform infrared, differential scanning calorimeter and cytotoxicity, and the release behaviors of drug molecules transporting through the polymers membranes were tested. Moreover, the effects of the polymers’ structures on the permeability were studied by molecular dynamic simulation. The simulation results showed that higher chains mobility and larger fractional free volume of the polymer membranes resulted in higher permeation rates. By comparing the monomers’ structure in the polymer materials, it was found that the polymer chains’ mobility decreases, and permeation rate correspondingly decreases with the increase in the amount and volume of side groups on the double bonds.

Formulation and evaluation of transdermal drug-delivery system of isosorbide dinitrate

The purpose of this study was to develop a reservoir-type transdermal delivery system for isosorbide dinitrate (ISDN). The developed patch consisted of five layers from bottom to top, namely, a temporary liner, an adhesive layer, a rate-controlling membrane, a reservoir and a backing. The effects of chemical penetration enhancers, reservoir materials and rate-controlling membranes on the release behaviour of ISDN from the transdermal patch were studied, and the in vitro release of ISDN from the developed patch was studied and compared with the commercially available ISDN patch. The results showed that there was no significant difference in permeation rates between the developed reservoir-type patch and the commercially available ISDN patch (p> 0.05). Moreover, the cumulative release ratio of the commercially available ISDN patch in 48 h was up to 89.8%, whereas the developed patch was only 34.9%, which meant the sustained release time of the developed patch was much longer than the commercially available ISDN patch, and would promote the satisfaction of the patient.