title: Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]-naphthyridinium salts from aaptamine.
abstract: The marine sponge constituent aaptamine (1) has been converted to the cancer cell growth inhibitor and antibiotic designated hystatin 2 (8a). Herein, we also report results of an initial SAR evaluation of new benzyl derivatives of aaptamine (1). Single benzylation was found to occur at nitrogen N-4 and led to the formation of the 4-benzylaaptamine derivatives 7a-c, whereas double benzylation gave the quaternary 1H-benzo[de][1,6]-naphthyridinium salts 8a-c. The anticancer and antimicrobial properties of these aaptamine derivatives are described. The quaternary ammonium salts 8a (hystatin 2) and 8b exhibited significant inhibitory activity against the murine P388 lymphocytic leukemia and a minipanel of human cancer cell lines. Salts 8a and 8b also had broad spectrum antimicrobial activities and were most potent against Mycobacterium tuberculosis, Neisseria gonorrhoeae, and Micrococcus luteus. Naphthyridinium chloride 8a was selected for further development, and results of an initial cell cycle analysis and a cDNA microarray study showed effects consistent with inhibition of the S-phase of cell growth.
authors.affiliation: Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Box 872404, Tempe, Arizona 85287-2404, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.forename: Holger
authors.initials: H
authors.lastname: Hoffmann
authors.forename: Delbert L
authors.initials: DL
authors.lastname: Herald
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Jean M
authors.initials: JM
authors.lastname: Schmidt
authors.forename: Yung
authors.initials: Y
authors.lastname: Chang
authors.forename: Robin K
authors.initials: RK
authors.lastname: Pettit
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D013329:Structure-Activity Relationship
chemical_list: C484866:1,4-bis(benzyl)-8,9-dimethoxy-4H-benzo(de)(1,6)naphthyridin-1-ium; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D009287:Naphthyridines; C043986:aaptamine