title: Antitumor activity of novel tricyclic pyrone analogs in murine leukemia cells in vitro.
abstract: New tricyclic pyrone derivatives were synthesized and tested for their ability to prevent L1210 leukemic cells from synthesizing DNA and growing in vitro. At 50 microM, a pyripyropene analog has no effect, whereas four pentahydro-3-aryl-1-oxopyrano[4,3-b][1]benzopyrans all inhibit DNA synthesis by 79-91% and tumor cell growth by 93-100%. These inhibitory effects are concentration dependent with IC50 around 8.5 microM for DNA synthesis at 2 hours and 1.1 microM for tumor cell growth at 4 days. The aryl groups of these antitumor agents are either 3,4-dimethoxyphenyl or 3-pyridyl. Introduction of a methyl group at C5a and a formyloxy or hydroxy group at C6 does not alter the antitumor effects of the 3,4-dimethoxyphenyl benzopyrans but reduces those of the 3-pyridyl benzopyrans, which, at 50 microM, inhibit DNA synthesis by only 32-49% and fail to alter tumor cell growth. The 4-hydroxy-6-(3-pyridyl)-2-pyrone has no effect and the tricyclic pyrones lacking aryl groups have very little inhibitory effects on DNA synthesis, suggesting that a greater conjugation is required for the antitumor activity. These molecules have never been reported and might be valuable to develop a new class of anticancer drugs.
authors.affiliation: Department of Chemistry, College of Veterinary Medicine, Kansas State University, Manhattan 66506, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Perchellet
authors.forename: S W
authors.initials: SW
authors.lastname: Newell
authors.forename: J B
authors.initials: JB
authors.lastname: Ladesich
authors.forename: E M
authors.initials: EM
authors.lastname: Perchellet
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: D H
authors.initials: DH
authors.lastname: Hua
authors.forename: S L
authors.initials: SL
authors.lastname: Kraft
authors.forename: R J
authors.initials: RJ
authors.lastname: Basaraba
authors.forename: S
authors.initials: S
authors.lastname: Omura
authors.forename: H
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000138:chemical synthesis; D007939:Leukemia L1210 / Q000188:drug therapy*; D011753:Pyrones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D011753:Pyrones