Nitrophenyl derivatives as aldose reductase inhibitors.

Nitrophenyl derivatives were recently discovered as a new class of ALR2 inhibitors by means of docking and database screening of the National Cancer Institute database of organic molecules. The nitro group was predicted to bind to the Tyr48 and His110 active site residues of the enzyme, the site where acidic ALR2 inhibitors such as carboxylic acids bind in their anionic form. Given the novelty of these compounds, we decided to expand their structure-activity relationships by synthesizing and testing a series of derivatives and the corresponding compounds having a carboxylic group instead of the nitro moiety; the results obtained were rationalized by means of docking and molecular dynamics simulations. On the whole there is an agreement between inhibitory data and the results of molecular modeling experiments, supporting the hypothesized binding mode of these compounds.

[1]  Conrad C. Huang,et al.  The MIDAS display system , 1988 .

[2]  G. Duclos.  New York 1987 , 2000 .

[3]  G. Rastelli,et al.  Synthesis, activity, and molecular modeling of a new series of tricyclic pyridazinones as selective aldose reductase inhibitors. , 1996, Journal of medicinal chemistry.

[4]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[5]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[6]  H. Berendsen,et al.  ALGORITHMS FOR MACROMOLECULAR DYNAMICS AND CONSTRAINT DYNAMICS , 1977 .

[7]  F A Quiocho,et al.  Structural features of the aldose reductase and aldehyde reductase inhibitor-binding sites. , 1998, Molecular vision.

[8]  F A Quiocho,et al.  Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Rastelli,et al.  1-Benzopyran-4-one antioxidants as aldose reductase inhibitors. , 1999, Journal of medicinal chemistry.

[10]  Peter A. Kollman,et al.  Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins , 1995, J. Comput. Chem..

[11]  A. Treasurywala,et al.  N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor. , 1984, Journal of medicinal chemistry.

[12]  M. Malamas,et al.  Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants. , 2000, Journal of medicinal chemistry.

[13]  C. Yabe-Nishimura,et al.  Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications. , 1998, Pharmacological reviews.

[14]  O. Schultz,et al.  Chemische Konstitution und pharmakologische Wirkung der Laxantien unter besonderer Berücksichtigung von Verbindungen mit zwei p‐Oxyphenyl‐Gruppen an einem gemeinsamen Kohlenstoffatom. 2. Mitteilung , 1958 .

[15]  L. Humber.  The medicinal chemistry of aldose reductase inhibitors. , 1987, Progress in medicinal chemistry.

[16]  Maria Cristina Gamberini,et al.  Discovery of new inhibitors of aldose reductase from molecular docking and database screening. , 2002, Bioorganic & medicinal chemistry.

[17]  G. Rastelli,et al.  Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase , 1997 .

[18]  D. Moras,et al.  Binding of aldose reductase inhibitors: correlation of crystallographic and mass spectrometric studies , 1999, Journal of the American Society for Mass Spectrometry.

[19]  D. Moras,et al.  A 'specificity' pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil. , 1997, Structure.

[20]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .