Synthesis and Biological Activities of Simplified Analogs of the NaturalPKCLigands, Bryostatin‐1 and Aplysiatoxin

Abstract

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.

Improved and large-scale synthesis of 10-methyl-aplog-1, a potential lead for an anticancer drug

“…The desired spiroketal (12) and undesired one (13) were obtained in 51e60% and 22e25% yields, respectively. Treatment of 13 with PPTS produced a 3:1 mixture of 12 and 13, and this equilibrium reaction was repeated again.…”

“…This structural simplification successfully eliminated over 20 synthetic steps and reduced barriers against its practical synthesis without attenuating its marked anti-proliferative activities and ability to activate PKCs. 12 Despite these prospective features as a future therapeutic candidate, the inefficiency of our first-generation synthesis of 1 prevented further experiments on animals and structural optimization for clinical use. To satisfy these needs, we attempted to develop a more practical synthetic method for 1 for the preparation of sufficient amounts of the sample in order to examine its toxicity and anticancer effects in an animal model.…”

The Phylum Bryozoa: From Biology to Biomedical Potential

“…Various authors already reviewed a large number of publications relating to the partial syntheses of bryostatins along with their bioactivities [220,231], with an emphasis on their effects on PKC signaling [139,232,233]. Pettit and colleagues performed a synthetic conversion of bryostatin-2 to bryostatin-1 [234] and, also, modified the chemical structure of bryostatin-2 in order to perform structure-activity relationship (SAR) analyses [235].…”

PKC in Regenerative Therapy: New Insights for Old Targets

“…Phorbol is a tetracyclic diterpene derived from the plant Croton tiglium L. In particular, phorbol 12,13-dibutyrate (PDBu) is an ester derivative with optimized potency and solubility which was employed to prove the importance of PKC in cell proliferation and cancer [70]. On the other hand, bryostatin-1 is a macrolide isolated from marine bryozoan Bugula neritina in 1967; considering the low efficiency of bryostatin extraction from its non-renewable natural sources and its challenging synthesis, researchers have produced a series of synthetic simplified analogues [71,72,73,74,75] (Figure 7). Among them, compound 3 has shown interesting selectivity toward novel PKC isoforms (δ, ε) [74].…”