Synthesis, physico-chemical characterization and theoretical studies on new amphiphilic extrinsically chiral porphyrin derivatives and their stereospecific self-assembly

Due to the pivotal role of porphyrins as building blocks for a rationalized self-assembly into supramolecular architectures and their ability to read and transfer the chiral information from the molecular to higher levels of organization, in this work, new amphiphilic porphyrin derivatives have been synthesized and their aggregation behaviour in aqueous environments has been theoretically modelled and experimentally studied. In particular, the role of a bile acid functionalization via an amidic bond at the C3 position was investigated and compared with the self-assembly behaviour of a non-covalent system, where the porphyrin and bile salt moieties interact as different entities. Remarkably, in this non-covalent condition, the interactions between the achiral 5-(4-carboxyphenyl)-10,15,20-(triphenyl)porphyrin (as free base or Zn(II) analogue), and the chiral bile salts sodium cholate (NaC) or deoxycholate (NaDC), using a porphyrin/bile salt (P/BS) molar ratio of 1/100, lead to a strong chirality reading out and amplification, with the formation of fibrillar elongated aggregates in aqueous solution buffered at alkaline pH. In the case of a covalent bile acid functionalization, conjugated molecules with different stereochemistry at the C3 position of the steroidal moiety (i.e. C3-α or C3-β) have been synthesized, following different synthetic strategies. From the analysis of the stereochemical effect in driving the aggregation, a completely different behaviour emerges. In fact, the C3-α conjugate is able to constitute mono- or multi-lamellar vesicular aggregates in aqueous solution, while the C3-β analogue tends to build suprastructures from tubules, to wrapped scrolls to wide superimposed flat sheets, that can be modulated by tuning the solvent composition and stoichiometry. Noteworthy, the different stereochemistry is also responsible for the selection of the chiral feature, resulting only the C3-β conjugates in remarkable circular dichroism (CD) bisignated bands. To carry on the exploration of the aggregation behaviour of amphiphilic porphyrin derivatives, a porphyrin-peptide conjugate has been synthesized via solid-phase peptide synthesis (SPPS), covalently linking to the porphyrin skeleton a tetrapeptide (a repeated sequence of D-valine and L-lysine) by means of an amidic bond with the carboxylic porphyrin group. In this case, the study of the aggregation behaviour revealed a strong dependence of the mechanism of aggregates formation on the conditions of solvent composition, pH and ionic strength, leading in PBS (phosphate saline buffer) solution to the homogeneous presence of partially formed tubular structures, showing a strong chirality induction at the supramolecular level. Furthermore, the positively charged lysine residues were considered relevant to potential applications in the field of antimicrobials and antimicrobial photodynamic therapy (aPDT). Preliminary applications of the novel molecules have been carried out. Specifically, stable porphyrin-based cubosomes formulations have been designed and characterized with the perspective of applicability in the field of PDT, exploiting the porphyrin ability to produce reactive oxygen species (ROS) and the biocompatibility of the bile acid or peptidic moiety. Antimicrobial tests have been conducted on the efficacy of the porphyrin-peptide derivative as antimicrobial agent towards Pseudomonas Aeruginosa. Finally, the interaction between the new porphyrin derivatives and silica nano-helices has been investigated, towards the construction of functional materials for the design of stereoselective sensing devices.