title: Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities.
abstract: Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (3), in which the C-1 ester group was replaced with an amide group, to improve chemical stability in vivo. Unfortunately, 3 exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10(-4) M. A conformational analysis and density functional theory calculations indicated that the stable conformation of 3 differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (1, 2) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10(-4) M, 3 may be an inactive control to identify the target proteins of aplogs.
authors.affiliation: a Division of Food Science and Biotechnology , Graduate School of Agriculture, Kyoto University , Kyoto , Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hanaki
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sugahara
authors.forename: Misako
authors.initials: M
authors.lastname: Aida
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008235:Lyngbya Toxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D007527:Isoenzymes; D008235:Lyngbya Toxins; C006610:aplysiatoxin; D051745:Protein Kinase C-delta
keywords: anti-proliferative; aplysiatoxin; protein kinase C; tumor promoter