aplysiatoxin and Neoplasms

Topics: Alkaloids; Animals; Cell Adhesion; Cell Aggregation; Cell Transformation, Neoplastic; Enzyme Induction; Humans; Isomerism; Lactones; Lyngbya Toxins; Marine Toxins; Mice; Mollusk Venoms; Neoplasms; Ornithine Decarboxylase; Phorbols; Tetradecanoylphorbol Acetate

Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Lyngbya Toxins; Models, Molecular; Neoplasms; Structure-Activity Relationship

Aplog-1 is a unique analog of tumor-promoting aplysiatoxin that inhibits tumor-promotion by phorbol diesters and proliferation of tumor cells. While the structural features relevant to the biological activities of Aplog-1 remain to be identified, recent studies by us have suggested that local hydrophobicity around the spiroketal moiety of Aplog-1 is a crucial determinant of its anti-proliferative activity. This hypothesis led us to design 12,12-dimethyl-Aplog-1 (3), in which a hydrophobic geminal dimethyl group is installed proximal to the spiroketal moiety to improve biological potency. As expected, 3 was more effective than Aplog-1 in inhibiting cancer cell growth and binding to protein kinase Cδ, a putative receptor responsible for the biological response of Aplog-1. Moreover, an induction test on Epstein-Barr virus early antigen demonstrated 3 to be a better anti-tumor promoter than Aplog-1. These results indicate that 3 is a superior derivative of Aplog-1, and thus a more promising lead for anti-cancer drugs.

Topics: Anticarcinogenic Agents; Antigens, Viral; B-Lymphocytes; Carcinogens; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Furans; Herpesvirus 4, Human; Humans; Hydrophobic and Hydrophilic Interactions; Lyngbya Toxins; Methylation; Neoplasms; Phorbol Esters; Protein Binding; Protein Kinase C-delta; Spiro Compounds; Structure-Activity Relationship

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.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Hydroxyl Radical; Lyngbya Toxins; Neoplasms; Protein Kinase C