Protein kinase C (PKC) is widely recognized as a therapeutic target in intractable diseases such as
cancer,
Alzheimer's disease (AD), and
acquired immune deficiency syndrome (
AIDS). While inhibition of PKC is a general therapeutic strategy for the treatment of
cancer, PKC activators are potential therapeutic agents for AD and
AIDS. However, concerns have been raised about their
therapeutic use since PKC activators such as
phorbol esters exhibit potent
tumor-promoting activities. Naturally occurring
bryostatin 1 (bryo-1),
prostratin, and 12-deoxyphorbol 13-phenylacetate (DPP) are fascinating PKC activators without
tumor-promoting activities. Bryo-1 is currently in clinical trials for the treatment of
cancer and is also effective against AD.
Prostratin and DPP are attractive candidates for the adjunctive treatment of human immunodeficiency virus (
HIV) infection. However, their limited availability from natural sources and synthetic complexity have hampered further development as therapeutic agents. We report here easy access (22 steps) to a simple analogue (1) of the
tumor-promoting
aplysiatoxin (ATX) as a novel PKC activator with anticancer and anti-
tumor-promoting activities. Anticancer activities of 1 against several human
cancer cell lines were comparable to those of bryo-1. Moreover, 1 as well as bryo-1 significantly inhibited the
Epstein-Barr virus early antigen (
EBV-EA) induction by the
tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), whereas ATX strongly induced
EBV-EA. This inhibitory effect is characteristic of antitumor promoters. Compound 1 as well as bryo-1 displayed significant binding and activation of PKCdelta and induced its translocation to the nuclear membrane in CHO-K1 cells. This study provides a synthetically accessible PKC activator with bryo-1-like activities, which could be another therapeutic lead for
cancer, AD, and
AIDS.