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

4-Substituted cyclohexanones. Predicting the facial selectivity of nucleophilic attacks from the geometrical changes on cation-carbonyl complexation: an ab initio investigation

This article does not have an abstract

3-Halocyclohexanones. Torsion angle changes after cation-carbonyl complexation dictate the facial selectivity in reactions with nucleophiles: an ab initio investigation

The geometrical changes that take place after complexation of the carbonyl oxygen of 3-halocyclohexanones with prototypical cations such as H<SUP>+</SUP> and Li<SUP>+</SUP> were calculated using ab initio MO methods at 6-31G level. The torsion angle changes interpret rationally the experimentally known axial preference of the 3-eq-derivatives and the axial preference (predicted from transition state calculations) of the 3-ax-species. Stereoelectronic effects in 3-ax-halocyclohexanones and 1,3-dipolar interactions in 3-eq-halocyclohexanones after complexation of the carbonyl oxygen with cations such as H<SUP>+</SUP> and Li<SUP>+</SUP> account for the experimentally observed and the predicted diastereoselectivities, respectively, of these molecules. The complexation induces pyramidalization of the carbonyl carbon and controls the p orbial to adopt an energetically favorable orientation (ax or eq) for capture by a nucleophile

Synthesis of nucleopeptides by employing an enzyme-labile urethane protecting group

Nucleoproteins are naturally occurring biopolymers in which the hydroxy group of a serine, a threonine, or a tyrosine moiety is linked through a phosphodiester group to the 3'- or 5'-end of a nucleic acid. For the study of the biological phenomena in which nucleo-proteins are involved, for example, viral replication, nucleopeptides embodying the characteristic linkage between the peptide chain and the oligonucleotide may serve as powerful tools. However, as a result of the multifunctionality and the pronounced acid and base lability of nucleopeptides, their synthesis requires the application of a variety of orthogonally stable blocking groups, which can be removed under the mildest conditions. We have developed a new mild enzymatic deprotection method, that is, the penicillin G acylase-catalyzed hydrolysis of the N- phenylacetoxybenzyloxycarbony (PhAcOZ) group, for the synthesis of nucleopeptides. We demonstrate the wide applicability of this method by coupling the N-terminally deprotected nucleopeptides 31 a-c with PhAcOZ-protected amino acids and subsequent removal of the N-PhAcOZ group from fully protected nucleotetrapeptides 32a,b with penicillin G acylase. The reaction conditions are very mild (pH 6.8) so that no undesired side reaction such as cleavage of the nucleotide bond or beta- elimination of the nucleotide was observed

Enzymatically cleavable linker groups in polymer-supported synthesis

Access to broadly applicable linker groups that are stable under a variety of reaction conditions and enable the release of target compounds from polymeric supports under the mildest conditions is a major goal in combinatorial chemistry. Here, we summarize the development of enzymatically cleavable linker groups used to prepare a variety of different target molecules on polymeric supports

Diastereofacial selectivities of substituted 5-aza-and 5-bora-2-adamantanones. Application of the complexation model and its ab initio MO investigation

N-Substituted 5-aza-2-adamantanones and 5-bora-2-adamantanone have been studied by ab initio MO methods at Becke3LYP level for their diastereofacial selectivities in reactions with nucleophiles by applying the complexation model. The facial predictions are fully consistent with the experiments. This is to be emphasized that in a given substrate there may be centres other than the carbonyl oxygen that may compete for the cation and, thus, contribute to the overall diastereodetermination. Other models such as the Cieplak model. Anh-Felkin model, and Houk model may or may not apply

The directional changes in torsion angles alone after complexation of the carbonyl oxygen with a prototypical cation such as H<SUP>+</SUP> predict the facial selectivity of substituted cyclohexanones. An ab initio investigation

H+ was taken as a prototypical cation for complexation with the carbonyl oxygen of 3-oxa-, 3,5-dioxa-, and 3-thiacyclohexanones. The geometries of the complexes were fully optimized using ab initio MO calculations with 6-31G basis set. The complexation desymmetrizes the molecular geometry further to an extent that the torsion angle changes on the axial face can be rationally used for the prediction of the facial selectivity in reactions with nucleophiles. The torsion angle changes are sensitive to the nature, position, and orientation of the substitutents. Based on the theory of stereoelectronic control and corroborated by ab initio MO calculations, a simple approach to the prediction of facial control in reactions of selected substituted cyclohexanones with nucleophiles is described. Some evidence is also presented against the known transition state models

The cation complexation model predicts the experimental π-facial selectivity of 2-ax-and 2-eq-substituted cyclohexanones. A detailed ab initio MO investigation

The geometrical changes on complexation of the carbonyl oxygen with prototypical cations such as H<SUP>+</SUP> and Li<SUP>+</SUP> are in tune with the polarity features of the C-X bonds in 2-ax-X-cyclohexanones (X=Cl, F, SR, OR; R=H, Me); the stereoelectronic effects apply. While the 2-ax-Cl- and 2-ax-SR-cyclohexanones are predicted to favor axial attacks, the 2-ax-OR- and 2-ax-F-cyclohexanones must capture a nucleophile predominantly from the eq-direction. The eq-selectivity of 2-ax-OR-cyclohexanone is in contradiction with the torsional model of Anh and Felkin. The Houk model will also fail due to the eminent steric interactions arising from the 2-ax-OMe function in the eq-TS. Neither the Anh-Felkin model nor the Cieplak model could be applied to 2-eq-MeO-cyclohexanone. The complexation model, however, predicts eq-selectivity in full agreement with experimental results. Second order perturbation theory analysis of the Fock matrix in NBO basis indicates that the role of the antiperiplanar effects is not as significant as perceived earlier by Cieplak and by Anh and Felkin