Feng Su

Synthesis and biological evaluation of sophoridinol derivatives as a novel family of potential anticancer agents.

New N-substituted sophoridinic acid/ester and sophoridinol derivatives were synthesized and evaluated for their cytotoxic activity in human HepG2 hepatoma cells from the lead sophoridine (1). Among the newly synthesized compounds, sophoridinol 7i displayed a potential antiproliferative activity with an IC50 of 3.1 μM. Importantly, it exerted an almost equipotent effect against both wild MCF-7 and adriamycin (AMD)-resistant MCF-7 (MCF-7/AMD) breast carcinoma cell lines. Its mode of action was to arrest the cell cycle at the G0/G1 phase, consistent with that of the parent 1. In addition, compound 7i also showed a reasonable ClogP value and favorable pharmacokinetic property with an area under the concentration-time curve (AUC) of 10.3 μM·h in rats, indicating an ideal druggable characteristic. We consider sophoridinol derivatives to be a novel family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.

In vitro biocompatibility evaluation of bioresorbable copolymers prepared from l-lactide, 1, 3-trimethylene carbonate, and glycolide for cardiovascular applications

PLLA-TMC-GA terpolymer was prepared by ring-opening polymerization of l-lactide, 1, 3-trimethylene carbonate (TMC), and glycolide (GA). The biocompatibility of terpolymer was evaluated in comparison with PLLA and PLLA-TMC with the aim of assessing their potential in the development of bioresorbable cardiovascular stents. Various aspects of in vitro biocompatibility were considered, including MTT assay, hemolytic test, dynamic clotting time, platelet adhesion, platelet activation, protein adsorption, plasma recalcification time and release of cytokines. The results revealed that the terpolymer presents good cytocompatibility and hemocompatibility. Moreover, no significant increase in the release of cytokines was detected. It is thus concluded that these polymers, in particular PLLA-TMC-GA terpolymer present good biocompatibility for cardiovascular applications.

Synthesis and structure−activity relationship of 8-substituted protoberberine derivatives as a novel class of antitubercular agents

BackgroundThe emergence of multi-drug resistant tuberculosis (MDR-TB) has heightened the need for new chemical classes and innovative strategies to tackle TB infections. It is urgent to discover new classes of molecules without cross-resistance with currently used antimycobacterial drugs.ResultsEighteen new 8-substituted protoberberine derivatives were synthesized and evaluated for their anti-mycobacterial activities against Mycobacterium tuberculosis (M. tuberculosis) strain H37Rv. Among them, compound 7g was the most effective antitubercular agent with minimum inhibitory concentration (MIC) of 0.5 μg/mL. Moreover, it also afforded a potent antitubercular effect against clinically isolated MDR strains of M. tuberculosis with MICs ranging from 0.25 to 1.0 μg/mL, suggesting a novel mode of action.ConclusionsThe structure−activity relationship (SAR) analysis revealed that introduction of a substituent at the 8-position in pseudoprotoberberine, especially an n-decyl, could significantly enhance the anti-TB activity. We consider 8-n-decylberberines to be a novel family of anti-tubercular agents with an advantage of inhibiting MDR strains of M. tuberculosis.

Rheological Properties, Drug Release Behavior and Cytocompatibility of Novel Hydrogels Prepared from Carboxymethyl Chitosan

Hydrogels were prepared by crosslinking carboxymethyl chitosan (CMCS) using 1-ethyl-3-(3-dimethylaminopropyl)-1-carbodiimide/N-hydroxysuccinimide (EDC/NHS) as catalyst under mild conditions. The resulting hydrogels present different crosslinking density, depending on the amount of EDC/NHS. Rheological studies show that hydrogels with high crosslinking density present higher storage modulus than those with low crosslinking density. A model drug, thymopentin (TP-5) is loaded in CMCS hydrogels. Parabolic release profiles are obtained in all cases. High crosslinking density hydrogels present slower release rate as compared to low crosslinking density ones because the former exhibits more compact structure. Preliminary studies were performed to evaluate the cytotoxicity of CMCS hydrogels by using MTT assay. Both cell morphology and RGR results show that the CMCS hydrogels present very low toxicity. Therefore, CMCS hydrogels are promising for applications in the fields of tissue engineering and controlled drug delivery.

Novel 12N-substituted matrinanes as potential anti-coxsackievirus agents

A series of novel 12N-substituted matrinane derivatives were synthesized and evaluated for their activities against coxsackievirus type B3 (CVB3) taking compound 1 as the lead. SAR analysis indicated that the introduction of a suitable heteroaromatic ring on the 12N-atom might be beneficial for the activity. Among them, compound 8a exhibited the highest potency against all CVB serotypes as well as CVA16 with IC50 values ranging from 2.02μM to 7.41μM, indicating a broad-spectrum anti-coxsackieviruse effect. Furthermore, compound 8a demonstrated a good safety profile in vivo. Thus, we consider 12N-substituted matrinanes to be a promising family of anti-coxsackievirus agents, and compound 8a to be a promising drug candidate in the treatment of various diseases related to coxsackievirus infection.

Self-assembled filomicelles prepared from polylactide-poly(ethylene glycol) diblock copolymers for sustained delivery of cycloprotoberberine derivatives

Polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers were synthesized by ring opening polymerization of l-lactide using a monomethoxy PEG (mPEG) as macroinitiator and zinc lactate as catalyst. The resulting diblock copolymers were characterized by 1H NMR and GPC. Polymeric micelles were prepared by self-assembly of copolymers in distilled water using co-solvent evaporation or membrane hydration methods. The resulting micelles are worm-like in shape as shown by TEM measurements. A hydrophobic anticancer drug, cycloprotoberberine derivative A35, was successfully loaded in PLA-PEG filomicelles with high encapsulation efficiency (above 88%). Berberine (BBR) was studied for comparison. In both methods, PLA-PEG filomicelles were prepared with a theoretical loading of 5%, 10% and 20%. Physical stability studies indicated that BBR/A35-loaded filomicelles were more stable when stored at 4 °C than at 25 °C. Compared with BBR-loaded filomicelles, A35-loaded filomicelles exhibited higher antitumor activity. Importantly, the in vitro cytotoxicity and stability of A35-loaded filomicelles evidenced the potential of drug-loaded filomicelles in the development of drug delivery systems.