Summary
We have carried out the organic synthesis of some of the natural products we have isolated, as well as their analogues. Although the main objective is to determine structure-reactivity relationships (SAR studies) in order to increase their biological activity and reduce potential side effects, the preparation of analogues has allowed us to develop other biotechnological applications.
Illustrative examples of the results obtained were:
Total synthesis of heterocycles. We successfully completed the total synthesis of various heterocyclic compounds with siderophore activity, such as piscibactin, and of an intermediate in its biosynthesis, prepisbactin, which we isolated for the first time from the fish-pathogenic bacterium Photobacterium damselae subsp. piscicida.
Semi-synthesis of cytotoxic steroids. We carried out the synthesis of various naturally occurring cytotoxic steroids: the first natural hydroxyminosteroids, which we had isolated from a sponge of the genus Cynachyrella. The profound chemomodulation performed on their structure resulted in the production of analogues that exhibited not only high but also selective cytotoxic activity, which were the subject of two patents; the synthesis of the cytotoxic parathiosteroids A-C from the soft coral Paragorgia sp and various analogues, such as the first natural steroids that possessed thioester and acetoamide groups in their side chains; and new analogues of cephalostatins and riterazines, which constitute one of the most potent antitumor compounds currently known, which were prepared from the cytotoxic steroid 22-epi-hippuristanol, which we isolated from the gorgonian Isis hipuris. In addition, we have prepared a chemical library of 63 analogues of withaferin A, a steroidal withanolide lactone with an ergosterol skeleton that possesses significant antitumor activity and is isolated from Withania somnifera and other plants belonging to the Solanaceae family. Their evaluation as cytotoxic agents allowed us to deduce numerous structure-activity relationships between this class of steroids.
Total synthesis of alkaloids. We performed total synthesis of the polychlorinated alkaloid dysithiazolamide isolated from the sponge of the genus Dysidea; of the enantiomer of acinetobactin from the pathogenic bacterium Aeromonas salmonicida subsp. salmonicida; of the nitrogenous compound N-acetyl homoagmatine obtained from the sponge Cliona celata; and synthetic approximations of the mycothiazol alkaloid isolated from the sponge Leiosella levis.
Total synthesis of nitrogenous terpenes. The total synthesis of the nitrogenous diterpene (-)-4-epiaxinyssamin, an analogue of axinyssamin from the sponge Axynissa ambrosia, was carried out. We have successfully completed the total synthesis of ircinialactam J, which we isolated from the sponge Ircinia felix and which has significant antiviral activity against human adenovirus (HAdV) with very low cytotoxicity, demonstrating an effectiveness 11 times greater than that of the standard drug cidofovir®.
New synthetic methodologies. In some cases, we have new synthetic methodologies, such as the novel preparation method of γ-hydroxy-α-nitroolefins by oxidation of α,β-epoxyketoximes with IBX and the application of the metathesis reaction in the synthesis of PN analogues (mycothiazol and hydroxyminosteroid dimers).