Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression

Oxidative cleavage of diethyldithioacetals by ammonium bromide promoted by (NH₄)₆Mo₇O₂₄.4H₂O-H₂O₂: A useful synthetic protocol for regeneration of carbonyl compounds^†

1039-1042Ammonium heptamolybdate promotes selective deprotection of a wide variety of diethyldithioacetals of aldehydes or ketones 1 into the parent carbonyl compounds 2, by ammonium bromide in presence of hydrogen peroxide and catalytic amount of perchloric acid at 0-5 °C in dichloromethane-water solvent system; mild conditions, high selectivity, good yield and easy work-up are some of the major advantages of the synthetic method

Chemoselective tetrahydropyranylation of primary alcohols under freezing water pressure

331-334A highly efficient environmentally friendly method for selective tetrahydropyranylation of primary alcoholic groups under pressure exerted by freezing water has been described

Lipase catalyzed kinetic resolution of <img src='/image/spc_char/alpha.gif' border=0> -phenyl-2-nitroalcohols

1961-1965It has been demonstrated that optically pure (S)--phenyl-2-nitroalcohols can be efficiently prepared by kinetic resolution of the corresponding 2-nitroalcohols involving amino lipase from Pseudomonas fluorescens. In the case of -phenyl-2-nitroalcohols, the corresponding (R)-acetates are also obtained in good optical and chemical yield along with the (S)-alcohols

Synthesis of the core structure of the lipoteichoic acid of streptococcus pneumoniae

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2-acetamino-4-amino-2,4,6-trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure GlcBeta(1-3)AATDgalBeta(1-3)GlcAlpha(1-O)DAG in a suitably protected form for further chain extension (lb, le) and as unprotected glycolipid (la) that was employed in biological studies. These studies revealed that la as well as 1 lead to interleukin-8 release, however not via TLR2 or TLR4 as receptor