Article

Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.

8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 05/2008; 51(7):2158-69. DOI: 10.1021/jm701447v
Source: PubMed

ABSTRACT Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.

1 Bookmark
 · 
90 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Forty eight 2-phenylnaphthalenoids were designed and successfully synthesized. Their in vitro cytotoxicities against the proliferations of MDA-MB-231, A549 and HeLa cell lines and inhibitory activities on DNA topoisomerase were evaluated. The quantitative structure-activity relationship (QSAR) studies were established on the basis of cytotoxicity data from MDA-MB-231 cell line. Among these compounds, compound 5 showed potent antiproliferative activity (IC50 = 1 μM) against MDA-MB-231 cells and inhibitory activity on topoisomeraseIIα. Further, in vivo antitumor study with xenograft nude mice indicated that compound 5 inhibited the growth of MDA-MB-231 cells and showed lower toxicity than etoposide (VP16). This work indicates that 2-phenylnaphthalenoids represent a novel type of TopoIIα-inhibitory scaffold for developing new antitumor chemotherapeutic agents.
    European Journal of Medicinal Chemistry 09/2014; 86C:782-796. · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Selective synthesis of functionalized naphthalenes and indenones by palladium-catalyzed cyclization of o-haloacetophenones and terminal alkynes in the presence of a secondary amine is reported. Under a nitrogen atmosphere, the palladium-catalyzed reaction of o-haloacetophenones with terminal alkynes in the presence of wet secondary aminesgenerated 1-(dialkylamino)-3-aryl/alkylnaphthalenes. When the reaction was conducted in air, 1-indenone-3-carbaldehydes were obtained. The synthesized β-arylnaphthalenes 4a–f emit light in a range from 386 to 452 nm with quantum yields from 0.10 to 0.48 in cyclohexane. The absorption and emission efficiency of 4d were finely tuned by the acidity of the environment, and this might be useful in the use of 4d as a fluorescent pH sensor.
    European Journal of Organic Chemistry 02/2012; 2012(4). · 3.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A new simple and efficient method for the synthesis of 2-phenylnaphthalenes from electron-rich 1-styryl-2-methoxybenzenes has been described. The reaction proceeds via TFA catalyzed C-C bond cleavage followed by intermolecular [4+2]-Diels-Alder cycloaddition of in situ formed styrenyl trifluoroacetate intermediate. The quantum chemical calculations identified the transition state for the cycloaddition reaction and helped in tracing reaction mechanism. The method has been efficiently utilized for synthesis of phenanthrene skeleton and a naphthalene-based potent and selective ER-β agonist.
    Chemical Communications 08/2014; 46(10). · 6.72 Impact Factor