Human Adenovirus (HAdV) infections in immunocompromised patients can result in
disseminated diseases with high morbidity and mortality rates due to the absence of
available treatments for these infections. Ircinia felix sponge was selected for the
significant anti-HAdV activity displayed by its organic extracts. Its chemical analysis
yielded three novel sesterterpene lactams, ircinialactams J-L, along with three known
sesterterpene furans which structures were established by a deep spectrometric
analysis. Ircinialactam J displayed significant antiviral activity against HAdV without
significant cytotoxicity, showing an effectiveness 11 times greater than that of the
standard treatment, cidofovir®. Some structure-activity relationships were deduced.
Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV
replicative cycle before HAdV genome reaches the nucleus of the host cell. The first
total synthesis of ircinialactam J was also accomplished to prove the structure and to
provide access to analogues. Key steps are a regio- and stereoselective construction
of the trisubstituted Z-olefin at Δ7 by iron-catalyzed carbometallation of a
homopropargylic alcohol, a stereoselective methylation to generate the stereogenic
center at C18, and the formation of the (Z)-Δ20 by stereoselective aldol condensation
to introduce the tetronic acid unit. Ircinialactam J is a promising antiviral drug against
HAdV infections.
