SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.
Structure elucidation of hyperibine J, a new polycyclic polyprenylated acylphloroglucinol isolated from Hypericum sp., was investigated. Molecular weight and spectroscopic data comparison with adhyperfirin (7‐deprenyl‐13‐methylhyperforin) declared a structure revision of the latter. Moreover, chemical transformation to hyperibone J confirmed its proposed structure and absolute configuration. Hyperibine J was found to be very similar to hyperforin and possesses a methyl substituent instead of a prenyl group at C‐1.
The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solubility, was used for this purpose. The solubility of many of the compounds was sufficiently improved to allow measurement of their respective dissociation constants (K). Parameters such as dissolution time, initial state of the solute (solid/liquid), co-solvent addition (DMSO and PEG3350), and sample filtration were evaluated. Except for filtration, the remaining parameters affected aqueous solubility, and a solubilization protocol was established according to these. The aqueous solubility of the 55 compounds in 5% DMSO was measured with this protocol, and a predictive quantitative structure property relationship model was developed and fully validated based on these data. This classification model separates the insoluble from the soluble compounds and predicts the solubility of potential small-molecule inhibitors of TNF-α in aqueous solution (containing 5% DMSO as co-solvent) with an accuracy of 81.2%. The domain of applicability of the model indicates the type of compounds for which estimation of aqueous solubility can be confidently predicted.
Isolation and Structure Elucidation of Hyperibine J [Revised Structure of Adhyperfirin (7-Deprenyl-13-methylhyperforin)]: Synthesis of Hyperibone J. -Structure elucidation of hyperibine J (I), a new polycyclic polyprenylated acylphloroglucinol isolated from Hypericum sp., is investigated. Molecular weight and spectroscopic data comparison with adhyperfirin declared a structure revision of the latter. Chemical transformation to hyperibone J (II) confirmed its proposed structure and absolute configuration. Hyperibine J was found to be very similar to hyperforin and possesses a methyl substituent instead of a prenyl group at C-1. -(MITSOPOULOU, K. P.; VIDALI, V. P.; MARANTI, A.; COULADOUROS*, E. A.; Eur. J. Org. Chem. 2015, 2, 287-290, http://dx.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.