A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity

Abstract

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.

Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

“…The synthesis of 3 was accomplished in a convergent approach from a spiroketal (6) 20) and carboxylic acid (5), as shown in Scheme 1. Compound 4 was prepared from Z-D-Asp(OtBu)-OH as reported previously, 28) and the subsequent removal of the t-butyl ester with trifluoroacetic acid (TFA) afforded the carboxylic acid (5).…”

“…The spiroketal 6 was synthesized from m-hydroxycinnamic acid in a similar manner to the synthesis of aplog-1. 20) Yamaguchi's esterification 29) of 6 with 5 provided 7. Oxidative cleavage of the olefin group, followed by esterification with N-hydroxysuccinimide, gave an activated ester.…”

“…The antiproliferative activity of aplog-1 against several cancer cell lines was previously shown to be similar to that of bryo-1. 20) Furthermore, aplog-1 behaved in a similar manner to bryo-1 rather than TPA for the translocation of GFP-tagged PKCδ using CHO-K1 cells; aplog-1 as well as bryo-1 translocated GFP-tagged PKCδ to the nuclear membrane and perinuclear region rather than to the plasma membrane, unlike TPA. 20) To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we recently synthesized 27-methyl and 27-methoxy derivatives (1, 2) that lacked the ability to bind to PKCδ and evaluated their anti-proliferative activities against 39 human cancer cell lines.…”

“…20) Furthermore, aplog-1 behaved in a similar manner to bryo-1 rather than TPA for the translocation of GFP-tagged PKCδ using CHO-K1 cells; aplog-1 as well as bryo-1 translocated GFP-tagged PKCδ to the nuclear membrane and perinuclear region rather than to the plasma membrane, unlike TPA. 20) To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we recently synthesized 27-methyl and 27-methoxy derivatives (1, 2) that lacked the ability to bind to PKCδ and evaluated their anti-proliferative activities against 39 human cancer cell lines. 21) Compounds 1 and 2 only exhibited weak anti-proliferative activities against all the human cancer cell lines tested, 21) suggesting that the activation of PKCδ was involved in growth inhibitory activities against several cancer cell lines that were at least sensitive to aplog-1.…”

“…18,19) As an alternative approach, we developed aplog-1, a simplified analog of ATX. 20) Aplog-1, supplied in only 27 steps via standard reactions, was not tumor-promoting or inflammatory, but was anti-proliferative even though it has the skeleton of tumor-promoting ATX. The antiproliferative activity of aplog-1 against several cancer cell lines was previously shown to be similar to that of bryo-1.…”