title: Biologically active heteroarotinoids exhibiting anticancer activity and decreased toxicity.
abstract: A series of retinoids, containing heteroatoms in a cyclic ring and called heteroarotinoids, were synthesized, and their biological activity was evaluated using tissue culture lines that have measurable responses to trans-retinoic acid (t-RA). Transglutaminase (TGase) was assessed in the human erythroleukemia cell line (GMO6141A) as an indicator of differentiation and apoptosis. Proliferation was evaluated in a human cervical cell line, CC-1, which exhibits dose-dependent alterations in growth rate in response to treatment with trans-retinoic acid. Activation of nuclear retinoic acid receptors was determined in a reporter cell line established from CC-1. The reporter line, called CC-B, contains a reporter gene controlled by a retinoic acid responsive element (RARE) and a thymidine kinase (tk) promoter. Treatment of the CC-B line with the heteroarotinoids resulted in a dose-responsive and retinoid-dependent regulation of reporter gene expression. The heteroarotinoids exhibited activity in all assays and correlated in a statistically significant manner between assays. RARE transactivation activity in CC-B cells correlated with induction of TGase in GMO6141A (R = 0.96) and with a decrease in the growth rate of CC-1 cells (R = -0.90). The ability of the selected heteroarotinoids to induce differentiation, inhibit proliferation, and activate nuclear receptors demonstrates the chemotherapeutic potential of these agents. In view of the biological activity cited, an in vivo toxicity study was conducted on male B6D2F1 mice with three heteroarotinoids, namely 8 [(2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimeth ylthiochroman-6-yl)-2,4,6-heptatrienoic acid], 10 [(2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimeth ylchroman-6-yl)-2, 4,6-heptatrienoic acid], and 13 [(E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoic acid]. The mice were used with gavage of heteroarotinoids in corn oil [0.1, 0.2, 0.4, or 0.8 mg/kg] and with 0.01 or 0.05 mg/kg of TTNPB (5) [(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]benzoic acid] as reference controls. The target organs affected in the mice by the three heteroarotinoids were those typically associated with t-RA (1) toxicity. The maximum tolerated dose (MTD) of 13 was 9.4 mg/kg/day, which was equal in toxicity to that of t-RA (1) and 1000-fold less toxic than TTNPB (5). The MTDs of 8 and 10 were 34 and 32 mg/kg/day, respectively, which is 3-fold less toxic than t-RA (1) and 3000-fold less toxic than TTNPB (5). The 3000-fold reduced toxicity, compared with only a 27% reduction biological activity of 8 and 10 with respect to that of TTNPB, observed in our assays indicates a good therapeutic ratio of these heteroarotinoids over the parent compound. The biological activity and reduced toxicity of these heteroartinoids demonstrate the potential efficacy as anticancer agents.
authors.affiliation: Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Benbrook
authors.forename: M M
authors.initials: MM
authors.lastname: Madler
authors.forename: L W
authors.initials: LW
authors.lastname: Spruce
authors.forename: P J
authors.initials: PJ
authors.lastname: Birckbichler
authors.forename: E C
authors.initials: EC
authors.lastname: Nelson
authors.forename: S
authors.initials: S
authors.lastname: Subramanian
authors.forename: G M
authors.initials: GM
authors.lastname: Weerasekare
authors.forename: J B
authors.initials: JB
authors.lastname: Gale
authors.forename: M K
authors.initials: MK
authors.lastname: Patterson
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: T C
authors.initials: TC
authors.lastname: Rowland
authors.forename: P
authors.initials: P
authors.lastname: DiSivestro
authors.forename: C
authors.initials: C
authors.lastname: Lindamood
authors.forename: D L
authors.initials: DL
authors.lastname: Hill
authors.forename: K D
authors.initials: KD
authors.lastname: Berlin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D012176:Retinoids