Simone Bonazzi

Anguinomycins and Derivatives: Total Syntheses, Modeling, and Biological Evaluation of the Inhibition of Nucleocytoplasmic Transport

The preparation of the polyketide natural products anguinomycin C and D is reported based on key steps such as Negishi stereoinversion cross coupling, Jacobsen Cr(III)-catalyzed Hetero Diels-Alder reaction, Evans B-mediated syn-aldol chemistry, and B-alkyl Suzuki-Miyaura cross coupling. The configuration of both natural products was established as (5R,10R,16R,18S,19R,20S). Biological evaluation demonstrated that these natural products are inhibitors of the nuclear export receptor CRM1, leading to shutdown of CRM1-mediated nuclear protein export at concentrations above 10 nM. Analogues of anguinomycin and leptomycin B (LMB) have been prepared, and the simple alpha,beta-unsaturated lactone analogue 4 with a truncated polyketide chain retains most of the biological activity (inhibition above 25 nM). The structural basis for this inhibition has been demonstrated by modeling the transport inhibitors into X-ray crystal structures, thus highlighting key points for successful and strong biological action of anguinomycin and LMB.

Antimicrobial Surfaces through Natural Product Hybrids

The power of two! A natural product hybrid (see structure) composed of a siderophore and an antibiotic separated by a poly(ethylene glycol) linker enables the preparation of antimicrobial and cell-resistant surfaces by a simple dip-and-rinse procedure. The anachelin siderophore (left) binds strongly to TiO2 surfaces, and vancomycin is responsible for antibiotic activity.

Protein-Resistant Surfaces through Mild Dopamine Surface Functionalization

The synthesis and evaluation of new dopamine-based catechol anchors coupled to poly(ethylene glycol) (PEG) for surface modification of TiO(2) are reported. Dopamine is modified by dimethylamine-methylene (7) or trimethylammonium-methylene (8) groups, and the preparation of mPEG-Glu didopamine polymer 11 is presented. All these PEG polymers allow stable adlayers on TiO(2) to be generated through mild dip-and-rinse procedures, as evaluated both by variable angle spectroscopic ellipsometry and X-ray photoelectron spectroscopy. The resulting surfaces substantially reduced protein adsorption upon exposure to full human serum.

Total Synthesis of (−)-Nakadomarin A

The convergent synthesis of the polycyclic alkaloid (-)-nakadomarin A (1) is reported. The synthesis plan identified macrocyclic lactam 4 as one of the important synthons (eight steps). The other synthon (five steps) was bicyclo[6.3.0] lactam 5 containing a single stereocenter that controlled all of the subsequent stereochemistry during the assembly process. A silyl triflate-promoted cascade of 4 and 5 was used to assemble the bulk of the alkaloid skeleton with the exception of the C5-C6 bond. The nakadomarin synthesis was then completed in one additional step.

Antimalarial and antitubercular nostocarboline and eudistomin derivatives: synthesis, in vitro and in vivo biological evaluation

The synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-Cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin N and O is reported. These compounds were evaluated in vitro against four parasites (Trypanosoma brucei rhodesiense STIB 900, Trypanosoma cruzi Tulahuen C2C4, Leishmania donovani MHOM-ET-67/L82 axenic amastigotes, and Plasmodium falciparum K1 strain), against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc(2)155 and Corynebacterium glutamicum ATCC13032, and cytotoxicity was determined against L6 rat myoblast cells. Nostocarboline and derivatives displayed potent and selective in vitro inhibition of P. falciparum with weak cytotoxicity. The dimers displayed submicromolar inhibition of L. donovani and T. brucei, and nanomolar activity against P. falciparum, albeit with pronounced cytotoxicity. One dimer showed a MIC(99) value against M. tuberculosis of 2.5 microg/ml. The alkylated eudistomin N and O derivatives displayed activities down to 18 nM against P. falciparum for N-Me Eudistomin N. Four dimers, nostocarboline and three eudostomin derivatives were evaluated in an in vivo Plasmodium berghei mouse model. No significant activity was observed for the dimers, but a 50% reduction in parasitaemia was observed at 4 x 50 mg/kg ip for nostocarboline.