Novel dual-mode antitumor chlorin-based derivatives as potent photosensitizers and histone deacetylase inhibitors for photodynamic therapy and chemotherapy.

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI.

Design, synthesis and biological evaluation of novel 3-hexyloxy chlorin e-based 15- or 13-amino acid derivatives as potent photosensitizers for photodynamic therapy.

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 3-hexyloxy chlorin e-based 15- or 13-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16-F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16-F10 cells.

Discovery of Novel Inhibitors and Fluorescent Probe Targeting NAMPT.

Nicotinamide phosphoribosyltransferase (NAMPT) is a promising antitumor target. Novel NAMPT inhibitors with diverse chemotypes are highly desirable for development of antitumor agents. Using high throughput screening system targeting NAMPT on a chemical library of 30000 small-molecules, we found a non-fluorescent compound F671-0003 and a fluorescent compound M049-0244 with excellent in vitro activity (IC50: 85 nM and 170 nM respectively) and anti-proliferative activity against HepG2 cells.

Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase.

Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.

Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation.

Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866).

[Recent advances in the study of new antifungal lead compounds].

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

A novel strategy for development of glucocorticoids through non-genomic mechanism.

Glucocorticoids (GCs) are routinely believed to take effect through genomic mechanisms, which are also largely responsible for GCs' side effects. Beneficial non-genomic effects of GCs have been reported as being independent of the genomic pathway. Here, we synthesized a new type of GCs, which took effect mainly via non-genomic mechanisms.

[Recent advances in the study of antifungal lead compounds with new chemical scaffolds].

In recent years, the incidence of infections caused by invasive fungal pathogens has increased dramatically. However, most antifungal agents used in clinic have many drawbacks and cannot meet the demand of the clinical use. Therefore, for the development of new generation of antifungal agents, it is of great significance to find antifungal lead compounds with novel chemical scaffolds and new mode of action.

Construction of a three-dimensional pharmacophore for Bcl-2 inhibitors by flexible docking and the multiple copy simultaneous search method.

B-Cell lymphoma-2 (Bcl-2) protein is a new promising target for anticancer drugs. A number of anticancer Bcl-2 inhibitors with diverse chemical structures have been discovered in recent years. In this paper, the flexible docking was performed to determine the binding modes of the representative inhibitors from different structural types.

Identification of Y118 amino acid residue in Candida albicans sterol 14alpha-demethylase associated with the enzyme activity and selective antifungal activity of azole analogues.

Our previous publication established a model to predict that the phenyl group of the C-3 side chain of azole antifungal compounds interacts with the phenol group of Tyr118 through the formation of pi-pi face-to-edge interaction. To verify this prediction, wild type and three site-directed mutants of the Y118 residue of Candida albicans sterol 14alpha-demethylase P450 (CACYP51) were constructed and heterologously expressed in Saccharomyces cerevisiae with deletion of the CYP51 gene. With the strains obtained and microsome enzymes separated, cell susceptibility and CACYP51 activity were examined with the 5 novel azole compounds based on the molecular modeling in comparison with fluconazole.

[Evolutionary trace analysis of N-myristoyltransferase family].

To clarify the important functional residues in the active site of N-myristoyltransferase (NMT), a novel antifungal drug target, and to guide the design of specific inhibitors, multiple sequence alignments were performed on the NMT family and thus evolutionary trace was constructed. The important functional residues in myristoyl CoA binding site, catalytic center and inhibitor binding site of NMT family were identified by ET analysis. The trace residues were mapped onto the active site of CaNMT.

[Synthesis and antifungal activity of novel triazole antifungal agents].

Aim: A series of triazole antifungal agents were synthesized to search for novel triazole antifungal agents with more potent activity, less toxicity and broader spectrum.

Methods: Twenty-one 1-(1H-1, 2, 4-triazolyl)-2-(2, 4-diflurophenyl)-3-(4-substituted-1-piperazinyl)-2-propanols were synthesized, on the basis of the three dimensional structure of P450 cytochrome 14alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated.

Results: Results of preliminary biological tests showed that most of title compounds exhibited activity against the eight common pathogenic fungi to some extent and the activities against deep fungi were higher than that against shallow fungi.

[Synthesis and antifungal activity of 1-(1,2,4-triazolyl-1H-1-yl)-2-(2,4-diflurophenyl)-3-(4-substituted benzyl-1-piperazinyl)-2-propanols].

Aim: A series of triazole antifungals were synthesized to search for novel triazole antifungals with more potent activity, less toxicity and broader spectrum.

Methods: Nineteen 1-(1,2,4-triazolyl-1H-1-yl)-2-(2,4-diflurophenyl)-3-(4-substituted benzyl-1-piperazinyl)-2-propanols were designed and synthesized, on basis of the three dimensional structure of P450 cytochrome 14 alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated.

Results: All the title compounds were first reported.