title: Conformationally restricted analogues of psorospermin: design, synthesis, and bioactivity of natural-product-related bisfuranoxanthones.
abstract: The antileukemic xanthone psorospermin is a topoisomerase II-dependent DNA alkylator in advanced preclinical development. Efforts have been made to further understand the structural requirements of its mechanism of action through the synthesis of ring-constrained analogues, based on the skeleton of the bisfuranoxanthone natural products. Molecules were designed that contain the bisfuran and xanthone portions of naturally occurring psorofebrins, and molecular modeling was used to assess their DNA alkylating potential and to refine the structures. A short, diastereoselective synthetic process to access bisfuranoxanthones was developed, culminating in the first total synthesis of (+/-)-isohydroxypsorofebrin. Two compounds designed and synthesized were of particular interest, chlorohydrin 7 and epoxide 6, which are reactive analogues of the natural product isohydroxypsorofebrin. The chlorohydrin retains the psorospermin-like DNA alkylation characteristics despite its rigid structure and high innate affinity for DNA. Molecular modeling has been used to rationalize the increased activity of the chlorohydrin. The chlorohydrin and epoxide show increased cytotoxicity compared to isohydroxypsorofebrin against a range of human tumor cell lines.
authors.affiliation: College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, Arizona 85721, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Dexheimer
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Lajos Z
authors.initials: LZ
authors.lastname: Szabo
authors.forename: Mary C
authors.initials: MC
authors.lastname: Gleason-Guzman
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005663:Furans; D044004:Xanthones; C025543:psorospermin; D004250:DNA Topoisomerases, Type II