Synthesis of natural compounds and bioactive congeners

(principal researchers, prof. Francesco De Riccardis and prof. Irene Izzo)

At our Organic Synthesis laboratory, the partial or total synthesis of over twenty compounds, including natural products and their analogues, some of which have potential anticancer and anti-inflammatory activity (Figure 1), has been carried out. In particular, the focus was directed toward the class of steroids and peptides, compounds that are essential to every living organisms. From a structural point of view, the most challenging task was the synthesis of azumamides, as evidenced by the cover of the journal Angewandte Chemie International Edition (Figure 2). 

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Figure 1. Significant examples of compounds synthesized.

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Figure 2. Cover on Angewandte Chemie.

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Synthesis of new steroidal and calixarene species as membrane pores

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In recent years, many research groups have dedicated their attention to the design and synthesis of compounds capable of behaving like membrane pores. This interest is justified by the fact that many antibacterial and antifungal drugs work by disrupting the chemo-osmotic balance of the plasma membrane of microorganisms, thereby inducing the death of the pathogens.

In this context, the design and synthesis of a polyhydroxysteroid dimer (which proved to be an efficient sodium transmembrane transporter) and the synthesis of compounds based on a cholestane core that feature one or two oligo-(ethylene glycol) units necessary for the exchange of electrolytes present both inside and outside the plasma membrane (Figure 3a) were undertaken. In these cases, the ion transport activity was comparable to that observed in amphotericin, a potent antifungal. The design and synthesis of a new class of compounds that feature a calix[4]arene core (Figure 4b) has generated several structural congeners, some with potent antitumor activity, enough to receive the cover of the Chemical Communications.

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Figure 3. Synthesis of new steroidal and calixarene species with membrane pore activity

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A new frontier: synthesis of cyclic peptoid foldamers

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Peptoids, N-substituted polyglycines, are peptidomimetics in which the side chains are attached to the nitrogen rather than the α carbon. Thanks to their structure, these compounds are stable to proteolysis and therefore advantageous for potential therapeutic applications. Since this polyamide backbone does not have the ability to form inter- and intramolecular hydrogen bonds of the N-H/O=C type, the conformational organization of such compounds is dictated by the substitution on the nitrogen and the related cyclization.

In order to understand the stabilizing effect of cyclization and complexation on the structure, extensive series of substituted cyclic tri-, tetra-, hexa-, octa-, and deca-oligoglycines have been synthesized (Figure 4a). For these compounds were conducted conformational studies, through computational analysis and X-ray spectroscopy, studies on complexation and ionic transport of alkali metals, investigations of gadolinium and iron(III) chelation. Antimicrobial, antitumor, antihelminthic and glycosidase inhibition activities were demostrated for several  macrocyclic derivatives. Moreover synthetic application in phase transfer catalysis were introduced.

Synthesis of the linear precursors of such cycles was carried out both in solid phase (chlorotrityl resin), using the sub-monomeric approach, introduced by Zuckermann, or the mixed submonomeric/monomeric approach, when proline or classical amino acid residues also needed to be incorporated. The precursors were then efficiently cyclized under high dilution conditions, using HATU (O-(7-hexafluorophosphate diazabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium) to activate the carboxylic function.

​Another interesting application of peptoids has been in the synthesis of oligomers capable of annealing with nucleic acids (DNA and RNA, Figure 4b). The first contribution in this regard came from the synthesis of iminodiacetic acid (IDA) derivatives and concerns a study conducted in collaboration with Prof. Albert Eschenmoser (from the Scripps Research Institute, La Jolla). Thymine-IDA derivatives were synthesized as plausible precursors of nucleic acids. Finally, N-(2-aminoethyl)thymine and N-(carboxymethyl) alternating peptoid residues were integrated into PNA fragments, a polyamide that mimics nucleic acids, to solve its poor water solubility issues. The synthesis of such oligomers was carried out by assembling them on a Rink resin.

Structural studies have shown that the structure of cyclic peptoids can evoke a conformational chirality that can be described in terms of the planar configuration of the tertiary amides (Figure 4c). It is interesting to note that the chirality of stereogenic centers (located in the side chain or within the same cycle) directly contributes to the definition of conformational chirality. Understanding how the chirality of stereogenic centers can influence the architectural arrangement of three-dimensional structures is one of the most complex and interesting challenges regarding cyclic peptoids.

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