Design, synthesis and biological evaluation of new embelin derivatives as CK2 inhibitors.

A new series of furan embelin derivatives was synthesized and characterized as ATP-competitive CK2 inhibitors. The new compounds were efficiently synthesized using a multicomponent approach from embelin (1), aldehydes and isonitriles through a Knoevenagel condensation/Michael addition/heterocyclization. Several compounds with inhibitory activities in the low micromolar or even submicromolar were identified. The most active derivative was compound 4l (2-(tert-butylamino)-3-(furan-3-yl)-5-hydroxy-6-undecylbenzofuran-4,7-dione) with an IC50 value of 0.63 µM. It turned out to be an ATP competitive CK2 inhibitor with a Ki value determined to be 0.48 µM. Docking studies allowed the identification of key ligand-CK2 interactions, which could help to further optimize this family of compounds as CK2 inhibitors.

Preparation and evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) nanoparticles.

In the present study, we developed the novel 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles (NPs) using the combination of sodium lauryl sulfate and poloxamer 407 as the anionic and non-ionic surfactant for stabilization. The PLGA NPs were prepared by emulsification/solvent evaporation method. Both the drug/polymer ratio and phase ratio were 1:10 (w/w). The optimized formulation of 17-AAG-loaded PLGA NPs had a particle size and polydispersity index of 151.6 ± 2.0 and 0.152 ± 0.010 nm, respectively, which was further supported by TEM image. The encapsulation efficiency and drug loading capacity were 69.9 and 7.0%, respectively. In vitro release study showed sustained release. When in vitro release data were fitted to Korsmeyer-Peppas model, the n value was 0.468, which suggested that the drug was released by anomalous or non-Fickian diffusion. In addition, 17-AAG-loaded PLGA NPs in 72 h, displayed approximately 60% cell viability reduction at 10 µg/ml 17-AAG concentration, in MCF-7 cell lines, indicating sustained release from NPs. Therefore, our results demonstrated that incorporation of 17-AAG into PLGA NPs could provide a novel effective nanocarrier for the treatment of cancer.

Synthesis and evaluation of analgesic and anti-inflammatory activities of most active free radical scavenging derivatives of embelin-A structure-activity relationship.

Antioxidant and related properties of the plant Embelia ribes and embelin are well known. In the present study embelin was condensed with various aromatic substituted primary amines to yield ten new and one reported derivatives along with monomethyl embelin. All these compounds along with embelin were evaluated for in vitro antioxidant activity using 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) and 2,2'-diphenyl-1-picryl hydrazyl (DPPH) methods. Two para-substituted embelin derivatives showed potent antioxidant activity. These compounds along with embelin were studied for analgesic and anti-inflammatory activities at 10 and 20 mg/kg doses by standard methods. Potent analgesic activity higher than the standard pentazocine was observed. Embelin and both of its derivatives almost completely abolished the acetic acid induced writhing. p-Sulfonylamine phenylamino derivative showed better anti-inflammatory activity than embelin.

Microwave-mediated Claisen rearrangement followed by phenol oxidation: a simple route to naturally occurring 1,4-benzoquinones. The first syntheses of verapliquinones A and B and panicein A.

The naturally occurring 1,4-benzoquinones 2-methoxy-6-propyl-1,4-benzoquinone (1), 2-methoxy-6-pentyl-1,4-benzoquinone (primin 2), 2-methoxy-6-pentadecyl-1,4-benzoquinone (3), 2-methoxy-6-heptadecyl-1,4-benzoquinone (dihydroirisquinone, pallasone B; 4) were synthesized by a simple protocol involving microwave accelerated Claisen rearrangement of allyl ethers 10, followed by hydrogenation of the side chain alkene, and oxidation to the quinone. The Claisen-based methodology was extended to the first synthesis of the marine benzoquinones verapliquinones A and B (5 and 6), and panicein A (7). Isoarnebifuranone (9) was also synthesized by a similar strategy.

Inhibitory effects of maesanin and analogs on arachidonic acid metabolizing enzymes.

The substituted 1,4-benzoquinone, maesanin (1), is a potent 5-lipoxygenase (5-LO) inhibitor present in the fruit of Maesa lanceolata Forssk. Thirteen natural, synthetic, semisynthetic, and microbially transformed analogs of 1 were tested for their in vitro inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase-1 (COX-1). Maesanin was the most active 5-LO inhibitor. All other analogs were inactive or less active than the natural products as 5-LO inhibitors. None of the tested compounds was strongly active in the COX-1 inhibition assay.

Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor.

A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2, 5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC(50) of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.

Total synthesis of ardisiaquinone A, a potent 5-lipoxygenase inhibitor, isolated from Ardisia sieboldii, and degree of 5-lipoxygenase inhibitory activity of its derivatives.

Ardisiaquinone A (1), isolated as a potent 5-lipoxygenase inhibitor from the woods of Ardisia sieboldii, has been synthesized efficiently via a cross-coupling reaction between the yne 5 and the iodide 6 derived from the common intermediate 4. Inhibitory activity for 1 and its derivatives is also reported.