Role of the phenolic hydroxyl group in the biological activities of simplified analogue of aplysiatoxin with antiproliferative activity

Abstract

The 18-deoxy derivative (3) of a simplified analogue (1) of aplysiatoxin with antiproliferative activity was synthesized to examine the role of the phenolic hydroxyl group at position 18 in the biological activities of 1. Compound 3 as well as 1 showed significant affinity for protein kinase Cδ (PKCδ), and the antiproliferative activity of 3 was slightly higher than that of 1. However, the anti-tumor-promoting activity of 3 was less than that of 1 in vitro, suggesting that the phenolic hydroxyl group of 1 is necessary for the anti-tumor-promoting activity but not for the binding of PKCδ and antiproliferative activity. Moreover, PKC isozyme selectivity of 3 was similar to that of 1, suggesting non-PKC receptors for these compounds to play some roles in the anti-tumor-promoting activity of 1.

Synthesis and Biological Evaluation of the 12,12-Dimethyl Derivative of Aplog-1, an Anti-Proliferative Analog of Tumor-Promoting Aplysiatoxin

“…10) Only weak EA-induction (9.0% and 7.1% at 10 À6 and 10 À7 M respectively) and significant suppression of TPA-induced EA production (5.0% and 7.2% at 10 À6 and 10 À7 M respectively) were observed, suggesting that 3 is a better anti-tumor promoter than Aplog-1. Although our previous study using 2 found no correlation between inhibition of TPA-induced EA production and suppression of proliferation of tumor cells, 14) introduction of the geminal dimethyl group into position 12 of Aplog-1 was found to enhance both activities.…”

“…21,22,24) We found previously that Aplog-1 displayed binding and activation profiles for PKC similar to those of Bryo-1, and that its antiproliferative activity was closely correlated with its affinity for PKC. 10,14) The affinity of 3 for PKC was measured in a competition binding assay with [ 3 H]phorbol 12,13-dibutyrate (PDBu). 25) Compound 3 exhibited strong affinity for PKC (K i ¼ 5:9 nM), about 2.5 times higher than that of Aplog-1 (K i ¼ 15 nM).…”

“…In subsequent efforts to identify the structural features relevant to the unique biological profile of Aplog-1, we synthesized 18-deoxy derivatives of Aplog-1 (1, 2). 10,14) Biological evaluation of them revealed the importance of the geminal dimethyl group at position 6 for antiproliferative activity and PKC binding of Aplog-1. This finding suggests that the spiroketal moiety of Aplog-1 is involved in the hydrophobic interaction with PKC, suggesting the possibility of enhancing the biological potency of Aplog-1 by increasing local hydrophobicity around the spiroketal moiety.…”

A New Lyngbyatoxin from the Hawaiian Cyanobacterium Moorea producens

“…Aplysiatoxin (ATX) and debromoaplysiatoxin (DATX) are 12- O -tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters which activate PKC as with lyngbyatoxin A ( 2 ) [6,29]. It was reported that K i values of ATX and DATX for binding to PKCδ-C1B are 0.41 nM [35,36] and 0.20 nM [37], respectively. These K i values are comparable to that of compound 2 obtained in this study.…”

Molecular Targets of Anticancer Agents from Filamentous Marine Cyanobacteria

“…27.7), with potent antiproliferative properties as potential anticancer agents [95][96][97][98][99][100][101][102][103]. These synthetic analogues have been shown to inhibit the action of tumor promotors as well as prevent growth of cancer cells in similar ways to bryostatin 1.…”