C3-Symmetric Ligands in Drug Design: When the Target Controls the Aesthetics of the Drug

Abstract

A number of proteins are able to adopt a homotrimeric spatial conformation. Among these structures, this feature appears as crucial for biologic targets, since it facilitates the design of C3-symmetric ligands that are especially suitable for displaying optimized ligand–target interactions and therapeutic benefits. Additionally, DNA as a therapeutic target, even if its conformation into a superhelix does not correspond to a C3-symmetry, can also take advantage of these C3-symmetric ligands for better interactions and therapeutic effects. For the moment, this opportunity appears to be under-exploited, but should become more frequent with the discovery of new homotrimeric targets such as the SARS-CoV2 spike protein. Besides their potential therapeutic interest, the synthetic access to these C3-symmetric ligands often leads to chemical challenges, although drug candidates with an aesthetic structure are generally obtained.

Molecular Spectroscopy Evidence of 1,3,5-Tris(4-carboxyphenyl)benzene Binding to DNA: Anticancer Potential along with the Comparative Binding Profile of Intercalation via Modeling Studies

“…C3-molecules have a structural moiety that is repeated three times around a rotational axis, just like C3-organisms and objects, and they can have an acyclic, exocyclic, macrocyclic, or bicyclic topology. The existence of a second rotational axis that goes in the opposite direction can occasionally complicate this C3-symmetry [ 19 ]. These substances are referred to as D3-symmetric.…”

An overview of the synthetic strategies ofC3-symmetric polymeric materials containing benzene and triazine cores and their biomedical applications

“…In addition, C 3-symmetric star-shaped molecules are applied in imaging cancer cells through fluorescence, as potent allosteric antagonists of P2X receptors, and in synthetic transport systems, besides their biological activities as antioxidants and antibacterials. 13–17 In view of these interesting applications, numerous C 3-symmetric aromatic molecules have piqued the interest of synthetic chemists and opened up new avenues for synthesis. Synthesis of certain molecules might begin with aldol-like events involving condensation of carbonyl compounds, cyclotrimerization reactions involving alkynes, or the functionalization of appropriately geared building blocks.…”

“…In addition, C3symmetric star-shaped molecules are applied in imaging cancer cells through uorescence, as potent allosteric antagonists of P2X receptors, and in synthetic transport systems, besides their biological activities as antioxidants and antibacterials. [13][14][15][16][17] In Maha A. Alshubramy is a PhD candidate in the Chemistry department at King Abdulaziz University. She obtained her master's degree in organic synthesis from Qassim University in 2020.…”