Design and Synthesis of Brefeldin A Sulfide Derivatives as Prodrug Candidates with Enhanced Aqueous Solubilities

Abstract

The addition of a variety of thiols to the alpha,beta-unsaturated lactone functionality present in brefeldin A has been carried out, and the resulting sulfides have been oxidized to the corresponding sulfoxides. These sulfoxides have the potential to undergo syn elimination to regenerate brefeldin A. The sulfoxides were more active than the sulfides as cytotoxic agents in a variety of human cancer cell cultures with the activities of the sulfoxides approaching that of brefeldin A itself. The cytotoxicities of the sulfoxides may be due to their conversion back to brefeldin A. The kinetics of sulfoxide elimination to form brefeldin A were studied in four cases, and the results indicate that substantial amounts of brefeldin A are likely to be generated during the cytotoxicity assays of the sulfoxide derivatives. Since the oxidation of sulfides to sulfoxides is a common metabolic reaction, the sulfides derived from brefeldin A can be considered as potential brefeldin A prodrugs. Several of the sulfide derivatives were determined to have enhanced aqueous solubilities relative to brefeldin A itself. A number of brefeldin A succinates, glutarates, oxidation products, and sulfone derivatives were also prepared and evaluated for cytotoxicity in cancer cell cultures. Some of the more active brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing cancer cell cultures were implanted subcutaneously (SC) and intraperitoneally (IP), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majority of these compounds, an observation which is consistent with the hypothesis that they are acting as brefeldin A prodrugs in vivo.

Cytotoxic activities of trichothecenes isolated from an endophytic fungus belonging to order hypocreales

“…Compound 1 was isolated originally from Penicillium decumbens under the name decumbin (Singleton et al, 1958) and later from several microorganisms. It was recognized initially that this compound has a wide range of antibiotic activities and has been studied as a potential anticancer and antiviral prodrug (Takatsuki et al, 1969;Argade et al, 1998a;Argade et al, 1998b;Fox et al, 2001).…”

Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling

“…This effect of BFA on ARF1 has detrimental consequences on several biological processes, including cell proliferation, cell migration, cell invasion, and cell signaling from the cell surface, both in normal and cancer cells [ 15 , 19 ]. Although the poor bioavailability of BFA precluded its use as anticancer drug [ 20 ], a great deal of effort has been placed into the synthesis of BFA analogues and derivatives [ 21 – 31 ], as well as into the finding and development of new ARF1 and ARF-GEF inhibitors [ 32 – 35 ]. This led, for instance, to the identification of Golgicide A (GCA) [ 36 ] and the development of LG186 [ 33 ], two potent and highly specific inhibitors of GBF1, a cis -Golgi ARF-GEF [ 37 ].…”

Abyssomicins from the South China Sea Deep‐Sea Sediment Verrucosispora sp.: Natural Thioether Michael Addition Adducts as Antitubercular Prodrugs

“…This view was based in part on a review of the literature, which confirmed that P450 enzymes can transform thioethers by way of sulfoxides into sulfones, and that sulfones can undergo a reverse Michael addition. For example, the synthetic vasodilator thioether flosequinan sulfide is transformed by rat and human liver P450 enzymes into its sulfoxide and sulfone,9 while cancer cell enzymatic oxidation of the synthetic thioether prodrugs of brefeldin yield sulfones, which in turn undergo rapid reverse Michael addition to deliver brefeldin 10. In yet another example of sulfone-mediated reverse Michael addition, the semisynthetic sulfone antibiotic dalfopristin undergoes metabolism in human plasma to give the natural product Michael acceptor pristinamycin IIA 11.…”