Rapid separation and purification of two C25 steroids with bicyclic [4.4.1] A/B rings from the marine fungus Aspergillus sp. LS116 by high-speed counter-current chromatography in stepwise elution mode.

Two C25 steroids with bicyclic [4.4.1] A/B rings were successfully separated from the marine fungus Aspergillus sp. LS116 by a two-step high-speed counter current chromatography (HSCCC). Petroleum ether/ethyl acetate/methanol/water (5.5:11:5:7, v/v) and petroleum ether/ethyl acetate/methanol/water (5:6:5:7, v/v) were selected as two optimum two-phase systems to purify two C25 steroids, neocyclocitrinol B (1) and threo-23-O-methylneocyclocitrinol (2). The purity of two compounds was over 94%. Their structures were determined by comprehensive spectroscopic techniques. This is the first report about rapid separation and identification of C25 steroids with bicyclic [4.4.1] A/B rings by HSCCC.

A Novel Ivermectin-Derived Compound D4 and Its Antimicrobial/Biofilm Properties against MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) and its biofilms infection is still a serious threat to global health. It is urgent to develop efficient drugs by repositioning or designing drugs to solve this problem. In this study, the antibacterial/biofilm activity and mechanisms of ivermectin (D) and its 4″-position amino substitution derivative (D4) against MRSA were investigated. The minimum inhibitory concentration (MIC) of D was 20 µg/mL, which is four times higher than D4 (MIC = 5 µg/mL). The mechanism research demonstrated that D4 was more potent than D at destroying bacterial cell wall, permeating cell membrane (6.25-36.0% vs 1.92-6.04%) and binding to MRSA genomic DNA. Moreover, after incubation with 10-40 µg/mL D4 for 24 h, the percentages of biofilm decreased by 21.2-92.9%, which was more effective than D (no significant change at 40 µg/mL). The antibiofilm effect is achieved by regulating the expression of related genes (RSH, relQ, rsbU, sigB, spA, and icaD). Additionally, though the higher hemolysis makes D4 a safety risk for intravenous injection, other administration options could be considered as well. Therefore, all the results have indicated that D4 may be a potential candidate compound for the treatment of MRSA and its biofilm infections.

Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents.

A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC50 value ranging from 0.82 to 0.91 µM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC50 values of 0.33 and 0.23 µM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.