Flap endonuclease-I (FEN-1) is involved in DNA repair and considered to be a novel target for the development of anticancer agents. N-hydroxy urea derivatives have been reported as FEN-1 inhibitors. To derive in vitro and in silico correlation, we have performed 2D-quantitative structure activity relationship (QSAR) analysis and docking studies on these compounds. 2D-QSAR models were developed using multiple linear regression (MLR) analysis and cross-validation using leave one out (LOO) method. The best model displayed R(2) of 0.806 and Q(2) of 0.607. Docking study revealed key interactions with desired amino acids and compare well with the in vitro potency of the reported compounds. Both studies reveal a link between FEN-1 inhibition and physicochemical descriptors or interactions with amino acids in active site. The information generated is first of its kind and may be helpful in the design of novel FEN-1 inhibitors.

2005-01-01·Bioorganic & medicinal chemistry letters4区 · 医学

The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors

4区 · 医学

Article

作者: Youssef L. Bennani ; Bayard Huck ; Sherry Boozer ; Daniel Silver ; Elizabeth Gleason ; L. Nathan Tumey ; Jianmin Wang ; David Bom ; Tom Dent ; Christina Leventhal ; Steven Murphy ; John Harrington ; Bruce Sherf ; Andrew Bailey ; Stephen Rundlett ; Kurt Brunden

Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.

Zhurnal Organicheskoi Khimii

Naphthalic acid derivatives. XI. General preparative method for preparing 1H-benzo[cd]indol-2-one derivatives by the reaction of N-(2,4-dinitrophenoxy)naphthalimide with alkalies

作者: Plakidin, V. L. ; Zadorozhnyi, N. M. ; Vostrova, V. N. ; Gnatyuk, P. P.

Reaction of naphthalimide derivatives I (R = H, 2-, 3-, and 4-MeO, Cl, and Br, 2-iodo, 3- and 4-NO₂) with aqueous and alc. NaOH gave 2,4-(O₂N)₂C₆H₃OH and II and/or III.I substituted in the 2- or 3-position of the naphthalene ring gave mixtures of II and III, whereas I (R = 4-MeO) gave III (R = 6-MeO) and I (R = 4-NO₂, Br, Cl) gave II (R = 5-NO₂,Br, Cl).Reaction of I (R = H) with amines, e.g., HOCH₂CH₂NH₂, (HOCH₂CH₂)₂NH, Et₂NH, gave N-hydroxynaphthalimide and 2,4-(O₂N)₂C₆H₃NR¹R² (R¹ = H, HOCH₂CH₂, R² = HOCH₂CH₂; R¹ = R² = Et).

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