Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation.

Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis. We successfully identified 6 compounds from a small molecule library through a structure-based virtual screening campaign and evaluated their enzymatic inhibitory potencies for PDK1-4. Our results indicated that compound 1 exhibited submicromolar inhibitory activities against PDK1-3 (IC50 = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC50 = 8.67 µM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC50 value of 10.7 µM. In addition, compound 1 induced cell apoptosis, arrested the cell cycle at the S phase, and reduced cell invasion and migration, while showing low in vivo toxicity at a high dose. Based on these observations, it can be concluded that compound 1 is a promising anti-PDK1-3 lead that merits further investigation.

Endophytic Fungus from Sinopodophyllum emodi (Wall.) Ying that Produces Podophyllotoxin.

The aryltetralin lactone podophyllotoxin, which exhibits pronounced antineoplastic activity, is used as the precursor of the following three clinical anticancer drugs: Etoposide™, Etopophos™ and Teniposide™. The natural occurrence of this arylnaphthalene lignan is scarce and unable to meet the ever-rising demand in the medical industry. Thus, developing alternative sources for the production of podophyllotoxin is extremely urgent. This is the first report of the production of podophyllotoxin from endophytic Alternaria tenuissima isolated from Sinopodophyllum emodi (Wall.) Ying. The identification of podophyllotoxin was performed using high-performance liquid chromatography and liquid chromatography-mass spectrometry (MS)-MS and confirmed by comparison with authentic standards.

An alkaloid and a steroid from the endophytic fungus Aspergillus fumigatus.

Two new compounds, fumitremorgin 12-methoxy-13-[5'-hydroxy-2'-(1''-hydroxy-3''-methoxy-5''-methylbenzoyl)-3'-methoxy]benzoic acid methyl ester (fumitremorgin D, 1) and 4,8,10,14-tetramethyl-6-acetoxy-14-[16-acetoxy-19-(20,21-dimethyl)-18-ene]-phenanthrene-1-ene-3,7-dione (2) were isolated from the cultured endophytic isolated fungus Aspergillus fumigatus, together with fourteen known compounds. Their structures were elucidated by 1-D and 2-D NMR analyses. The cytotoxicity profile of the compound against the human hepatocellular carcinoma cell line HepG2 was evaluated by MTT antiproliferative assays.

New lignans and their biological activities.

Lignans, which are widely distributed in higher plants, represent a vast and rather diverse group of phenylpropane derivatives. They have attracted considerable attention due to their pharmacological activities. Some of the lignans have been developed approved therapeutics, and others are considered as lead structures for new drugs. This article is based on our previous review of lignans discovered in the period 2000-2004, and it provides a comprehensive compilation of the 354 new naturally occurring lignans obtained from 61 plant families between 2005 and 2011. We classified five main types according to their structural features, and provided the details of their sources, some typical structures, and diverse biological activities. A tabular compilation of the novel lignans by species is presented at the end. A total of 144 references were considered for this review.