title: Synthesis and biological evaluation of the 12,12-dimethyl derivative of Aplog-1, an anti-proliferative analog of tumor-promoting aplysiatoxin.
abstract: 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.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kikumori
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000956:Antigens, Viral / Q000032:analysis* / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000473:pathology / Q000821:virology*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008235:Lyngbya Toxins / Q000009:adverse effects* / Q000494:pharmacology; D008745:Methylation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D010703:Phorbol Esters / Q000009:adverse effects / Q000494:pharmacology; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016588:Anticarcinogenic Agents; D000956:Antigens, Viral; D002273:Carcinogens; C033305:Epstein-Barr virus early antigen; D005663:Furans; D008235:Lyngbya Toxins; D010703:Phorbol Esters; D013141:Spiro Compounds; C520774:spiroketal; C006610:aplysiatoxin; D051745:Protein Kinase C-delta