Five-fold symmetric penta-bioconjugated corannulenes : synthesis, properties and applications

Abstract

Corannulene is a C5v symmetric polyaromatic hydrocarbon (PAH) and it can be considered the smallest fragment of buckminsterfullerene that displays a curvature of the carbon skeleton, which gives corannulene interesting physical properties differing from those of planar -conjugated analogs (i.e. bowl-shaped structure, rapid bowl-to-bowl inversion at room temperature and a dipole moment). With the advent of corannulene in kilogram scale, and a robust procedure for converting corannulene into sym-pentachlorocorannulene, came the motivation to create an array of 5-fold symmetric pentasubstituted corannulene derivatives suitable for incorporation into polymers, materials, bioconjugates and supramolecular architectures. The development of a robust synthetic pathway for the preparation of C5-symmetric pentasubstituted corannulenes functionalized with the main classes of biomolecules (carbohydrates, oligopeptide, lipids and nucleic acids) and their applications and properties are described in this dissertation. The first goal is having access to a library of sym-pentasubstituted corannulene derivatives bearing a broad window of functional groups and displaying high solubility in organic solvents. Iron- catalyzed alkyl-aryl cross-coupling and further elementary chemical reactions allow the synthesis in hundreds of milligrams scale of a wide range of penta-substituted corannulenes displaying the principal organic functional groups. Copper nanoparticles catalyzed and microwave assisted CuAAC “click” reaction provides optimal reaction conditions for the conjugation of sym-penta-(1-butyn-4-yl)-corannulene with azide- containing biomolecules; corannulene derivatives bearing nucleosides (thymidine and deoxy- adenosine), sugars (ribose and galactose), short oligopeptide and lipids can be prepared in good yield and purity. In the case of the synthesis of sym-penta-(DNA) corannulene, the CuAAC reaction conditions need to be optimized using CuBr-TBTA as catalytic species. The assembling behavior of these molecules and the computational studies for the formation of supramolecular architectures are described in this dissertation. Cholera toxin (CT) from Vibrio cholerae belongs to the AB5 bacterial toxins family. Following the “Finger-Linker-Core” approach, several five-fold symmetric pentasubstituted corannulene derivatives conjugated to PEG-like chains functionalized with CT binders galactose and GM1os are synthesized and their inhibition potency toward CT evaluated. The synthesized GM1os-based inhibitors show high binding to CT with IC50 values in the range of nanomolar concentrations. Several pentakis-lipido corannulene derivatives displaying different aliphatic chains are synthesized and their thermal and gelation behaviors investigated. While oleyl-functionalized corannulene derivative exists in a lamellar liquid-crystalline phase at room temperature and shows gelator properties, the saturated analog is partially crystallized at room temperature but forms gel in cyclohexane; heptyl-functionalized corannulene does not show neither gelator nor liquid-crystalline behavior. The results suggest that the length and geometry of the alkyl chains attached onto corannulene play an important role on the physical properties of pentakis-lipido corannulenes. In summary, this PhD dissertation describes the development of a powerful “toolbox” for the synthesis of C5-symmetryc pentasubstituted corannulene derivatives, which can find application in biology, pharmacology, material chemistry, polymers and supramolecular chemistry.