Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity

• Published in: Journal of medicinal chemistry Vol. 55; no. 11; pp. 5614 - 5626
• Main Authors: Kikumori, Masayuki, Yanagita, Ryo C, Tokuda, Harukuni, Suzuki, Nobutaka, Nagai, Hiroshi, Suenaga, Kiyotake, Irie, Kazuhiro
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.06.2012; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Carcinogens - chemical synthesis; Carcinogens - pharmacology; Carcinogens - toxicity; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Hydrophobic and Hydrophilic Interactions; Isoenzymes - metabolism; Life Sciences & Biomedicine; Lyngbya Toxins - chemical synthesis; Lyngbya Toxins - pharmacology; Lyngbya Toxins - toxicity; Male; Mice; Mice, Inbred ICR; Pharmacology & Pharmacy; Protein Binding; Protein Kinase C - metabolism; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - pharmacology; Spiro Compounds - toxicity; Structure-Activity Relationship; PROTEIN-KINASE-C; PHASE-II TRIAL; TUMOR-PROMOTING APLYSIATOXIN; THERAPEUTIC TARGET; EPSTEIN-BARR VIRUS; CATALYTIC ASYMMETRIC ALLYLATION; BRYOSTATIN 1; PHORBOL ESTER BINDING; SEQUENTIAL PACLITAXEL; TRANSGENIC MICE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300566h

Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K i values, approximately 10–20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.