Xinyang Wang

Novel pleuromutilin derivatives as antibacterial agents: Synthesis, biological evaluation and molecular docking studies

Owing to the increasingly serious problems caused by multidrug resistance in community-acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. In this paper, we describe the design and synthesis of novel pleuromutilin derivatives containing the (2-aminothiazol-4-yl)-4-methyl group, as well as their in vitro antibacterial activities against Gram-positive clinical bacteria. Most of the tested compounds displayed strong antibacterial activities against these methicillin-susceptible and methicillin-resistant bacteria. Particularly noteworthy compound 15 and its derivative 16e, both showed potent antibacterial properties (0.0625-0.5μg/mL) that are superior to amoxicillin and tiamulin. Molecular docking studies suggested that the amino thiazole ring on the side chains of the pleuromutilin derivatives can in general be accommodated near the mutilin core in the binding pocket, and thus play an important role in the activity of the whole molecule. The findings reported herein may provide a new insight into the design of novel pleuromutilin derivatives for human clinical use.

Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera. Cytotoxic activity of the metabolites against human prostate cancer cells

Biotransformation of 20(S)-protopanaxadiol (1) by the fungus Absidia corymbifera AS 3.3387 yielded five metabolites (2-6). On the basis of spectroscopic data analyses, the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23, 24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25-hydroxyl-20(S)-protopanaxadiol (4), 7β-hydroxyl-20(S)-protopanaxatriol (5), and 7-oxo-20(S)-protopanaxatriol (6), respectively. Among them, 5 and 6 are new compounds. These results indicated that A. corymbifera AS 3.3387 could catalyze the side-chain oxidation-reduction, 7β hydroxylation, and the specific C-7 dehydrogenation of derivatives of 20(S)-protopanaxadiol. The metabolites 2, 5, and 6 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.

Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents

Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amide 10f was the most active, with IC₅₀s of 3.78-7.63 μM against all tested cancer cells, even more potent than sorafenib (9.12-22.9 μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.

Synthesis and biological evaluation of nitric oxide-releasing hybrids from gemcitabine and phenylsulfonyl furoxans as anti-tumor agents

A series of novel hybrids 10a–m were designed and synthesized by coupling phenylsulfonyl furoxans with gemcitabine through various diols or alcohol amine linkers, and their biological activities were evaluated in vitro. Most of the hybrids exhibited good to moderate anti-tumor activities, which are associated with NO release. In particular, hybrid 10e showed excellent anticancer activities which were more potent than or comparable to gemcitabine. However, inhibition of nucleoside transport only significantly decreased the inhibitory rates of gemcitabine against HepG2 cells but not 10e, and the inhibitory rates of 10e were partially reduced by pre-treatment with hemoglobin, demonstrating that the anti-tumor activity of 10e might result from the synergic effect of high levels of NO production and gemcitabine fragment. In addition, compound 10ecould apparently induce cell apoptosis by regulating apoptotic relative proteins. Therefore, our novel findings provide a proof of principle in the design of new furoxan/gemcitabine hybrids for the intervention of human cancers.

Design, Synthesis, and Antibacterial Activity of Novel Pleuromutilin Derivatives Bearing an Amino Thiazolyl Ring

A series of novel pleuromutilin derivatives containing the amino thiazolyl ring were designed, synthesized, and evaluated for their antibacterial activities in vitro against Gram‐positive clinical bacteria. All the target compounds showed better aqueous solubility compared with the lead compound (10). Most compounds displayed strong antibacterial activities against both susceptible and resistant bacteria, particularly for the compound (12f) which showed extraordinary antibacterial properties superior to amoxicillin and tiamulin. Molecular docking studies revealed that the amino thiazolyl ring, the side chains of the pleuromutilin derivatives, can be adopted in the binding pocket of the 50S ribosomal subunit near the mutilin core. Therefore, our novel findings may provide new insights into the design of novel pleuromutilin derivatives and lay the basis for further studies on these promising antibiotics for human clinical use.

Design and Synthesis of C3‐Substituted β‐Carboline‐Based Histone Deacetylase Inhibitors with Potent Antitumor Activities

A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β‐carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low‐micromolar range. In particular, the HDAC inhibition IC50 value of N‐(2‐(dimethylamino)ethyl)‐N‐(4‐(hydroxylcarbamoyl)benzyl)‐1‐(4‐methoxyphenyl)‐9H‐pyrido[3,4‐b]indole‐3‐carboxamide (9 h) is five‐fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat). Furthermore, 9 h was found to increase the acetylation of histone H3 and α‐tubulin, and to induce DNA damage as evidenced by hypochromism and enhanced phosphorylation of histone H2AX. Compound 9 h inhibits Stat3, Akt, and ERK signaling, important cell‐growth‐promoting pathways that are aberrantly activated in most cancers. Finally, 9 h showed reasonable solubility and permeability in Caco‐2 cells. Our findings suggest that these novel β‐carboline‐based HDAC inhibitors may hold great promise as therapeutic agents for the treatment of human cancers.

Synthesis and Biological Evaluation of Novel Farnesylthiosalicylic Acid Derivatives for Cancer Treatment

Novel farnesylthiosalicylic acid (FTS) derivatives were synthesized by coupling with different substituted diamines. Their in vitro growth inhibitory activities against seven human cancer cell lines were evaluated. The results revealed that the synthetic farnesylthiosalicylamides displayed significant antitumor activities compared to the positive control FTS. Especially, compound 8f exhibited the strongest antitumor activities with IC50 values of 6.20–7.83 µM, which were one‐ to threefold less than those of sorafenib and six‐ to tenfold less than that of FTS against each cell line in vitro. Furthermore, 8f could inhibit the Ras‐related signaling pathway and induce SMMC‐7721 cell apoptosis superior to FTS in a dose‐dependent manner. These data indicate that 8f may hold greater promise as therapeutic agent for the intervention of human cancers.

Hybrid molecule from Farnesylthiosalicylic acid-diamine and phenylpropenoic acid as Ras-related signaling inhibitor with potent antitumor activities.

Novel series of Farnesylthiosalicylic acid‐diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12f dose‐dependently induced SMMC‐7721 cell apoptosis. Additionally, our observations demonstrated that 12f inhibited both Ras‐related signaling and phosphorylated NF‐κB synergistically, which may be advantageous to the strong antitumor activities of 12f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.

Novel FTS-diamine/cinnamic acid hybrids inhibit tumor cell proliferation and migration and promote apoptosis via blocking Ras-related signaling in vitro

Novel FTS-diamine/cinnamic acid hybrids 7a–f were prepared, and their in vitro biological activities were evaluated. It was found that 7c showed the strongest anti-proliferation activities against cancer cells in vitro and significant growth inhibition of tumor in vivo, and more potential for inhibitory selectivity to tumor cells than intermediate 6 and FTS. Furthermore, the anti-proliferative effect of 7c in Lovo cell lines followed a similar pattern, which included a dose-dependent induction of cell apoptosis via the up-regulation of Bax as well as activated caspase-3 and down-regulation of Bcl-2, and the inhibition of cancer cells migration and invasion in a concentration-dependent way. More importantly, 7c could significantly block Ras-related signaling pathways, which may contribute to its pro-apoptotic induction of the cancer cell lines and its inhibition of carcinoma cell proliferation, migration, and invasion. Therefore, our novel findings may provide a new framework for the discovery of new FTS hybrids for the intervention of human carcinoma cells.