Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para‐Phenyl Bioisosteres

Abstract

Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…If the para ‐substituted arene of the drug molecule influences the conformation of the molecule or has a role in the pharmacophore (e.g., π–π staking)—an aliphatic bioisostere will not be effective. It was shown that BCP improves aqueous solubility by at least 50‐fold and markedly decreases nonspecific binding (NSB) . On the other hand, BCO increased the lipophilicity of the molecules but did not show the same benefits regarding NSB or solubility.…”

“…A number of different tyrosine 325 h and phenylalanine 325 g derivatives have also been reported in the literature . BCP analogues of these natural amino acids were made to elucidate conformational and electronic effects in peptides.…”

“…BCP analogues of these natural amino acids were made to elucidate conformational and electronic effects in peptides. The BCP‐containing glycine derivative was synthesized through the homologation of a carboxylic acid, followed by a Strecker reaction, in eight steps . The BCP‐containing tyrosine analogue was accessed from the BCP aldehyde by a Wittig reaction to form an α,β‐unsaturated ester, this group was then transformed into a diazo derivative by using hydrohydrazination conditions …”

“…In addition, further hyperconjugation,v icinal throughb ond s CaCb !p* could be the reason for the notable stabilityo ft he cubane cation. [122] Furthermore, Eaton et al pointedo ut another consideration: the internuclearl ine between the individualc arbon bondsr epresents af alse pictureo ft he actually bent bond ("banana bond"), [123] since the endocyclic interorbital angle is rather 101-1048 than 908, [124] reducing the actual pyramidalization angle. [122] Further influences on the solvolysis rate are reported for substituted cubanes.…”

Toward Resolving the Resveratrol Conundrum: Synthesis and in Vivo Pharmacokinetic Evaluation of BCP–Resveratrol

“…Next, in the key-step of this protocol, the olefin in 20 was subjected to Carriera hydrohydrazination conditions to generate the diazo compound 21. 22 Deprotection of the Boc functionality with trifluoroacetic acid gave the hydrazine intermediate, which in turn could be converted to the amine 22 with the help of samarium diiodide. Finally, acid hydrolysis of 22 yielded the hydrolyzed product 23 to complete our racemic synthesis of thetyrosine-BCP ethyl ester.…”