title: Cytotoxic activity of azulenequinones against human oral tumor cell lines.
abstract: We investigated twenty-seven azulenequinone derivatives for their relative cytotoxicity against three human normal cell lines (HGF, HPC, HPLF) and four human tumor cell lines (HSG, HSC-2, HSC-3, HL-60). Parent 1,5-azulenequinone showed potent and some tumor-specific cytotoxicity. Halogenated derivatives of 1,5- and 1,7-azulenequinone showed potent cytotoxicity, but lower tumor-specific cytotoxicity. In contrast to other azulenequinones, amino derivatives such as 3-amino-1,5- and 1, 7-azulenequinones showed relatively lower cytotoxic activity. The 3-Phenoxy-1,5-azuleneqinone derivative showed higher cytotoxicity than the 3-phenoxy-1, 7-azulenequinone derivative. 1,5- and 1,7-Azulenequinones generally showed higher cytotoxicity, as compared with tropolones and azulene derivatives. 3- (3-Guaiazulenyl)-1, 5-azulenequinone [12] and 7-isopropyl-3- (4-methylanilino)-2-methyl- 1, 5-azulenequinone [24] showed a relatively higher TS value and induced apoptosis (internucleosomal DNA fragmentation, activation of caspases 3, 8 and 9) in HL-60 and HSC-2 cells, possibly via the activation of both mitochondria-independent (extrinsic) and -dependent (intrinsic) pathways. Western blot analysis showed that [24] slightly increased the intracellular concentration of pro-apoptotic proteins (Bad, Bax) in HSC-2 cells, whereas [12] was much less active. None of the twenty-seven azulenequinones showed anti-HIV activity. These results suggest [12] and [24] as possible candidates for future cancer chemotherapy.
authors.affiliation: Faculty of Science, Josai University, Sakado, Saitama, Japan. hwaka@josai.ac.jp
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishishiro
authors.forename: Satomi
authors.initials: S
authors.lastname: Arikawa
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Kurihara
authors.forename: Shigemi
authors.initials: S
authors.lastname: Terakubo
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shoji
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D052176:Azulenes; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003508:Cycloheptanes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1; D018922:HL-60 Cells; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011809:Quinones / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D052176:Azulenes; D003508:Cycloheptanes; D011809:Quinones; C005525:azulene