title: Structure-activity studies on the side chain of a simplified analog of aplysiatoxin (aplog-1) with anti-proliferative activity.
abstract: We have recently developed a simplified analog of aplysiatoxin (aplog-1) as an activator of protein kinase C (PKC) with anti-proliferative activity like bryostain 1. To identify sites in aplog-1 that could be readily modified to optimize therapeutic performance and to develop a molecular probe for examining the analog's mode of action, substituent effects on the phenol ring were systematically examined. Whereas hydrophilic acetamido derivatives were less active than aplog-1 in inhibiting cancer cell growth and binding to PKCδ, introduction of hydrophobic bromine and iodine atoms enhanced both biological activities. The anti-proliferative activity was found to correlate closely with molecular hydrophobicity, and maximal activity was observed at a logP value of 4.0-4.5. On the other hand, an induction test with Epstein-Barr virus early antigen demonstrated that these derivatives have less tumor-promoting activity in vitro than aplog-1 regardless of the hydrophobicity of their substituents. These results would facilitate rapid preparation of molecular probes to examine the mechanism of the unique biological activities of aplog-1.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kamachi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008235:Lyngbya Toxins / Q000737:chemistry* / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008235:Lyngbya Toxins; C006610:aplysiatoxin; D011493:Protein Kinase C