Synthetic atpenin analogs: Potent mitochondrial inhibitors of mammalian and fungal succinate-ubiquinone oxidoreductase

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 5, 2010, Pages 1665-1668

  Selby, Thomas P ^a   Hughes, Kenneth A ^a   Rauh, James J ^a   Hanna, Wayne S ^a  

^a DUPONT COMPANY   (United States)

Author keywords

Complex II inhibition; Mitochondrial electron transport; Pentasubstituted pyridines; Succinate ubiquinone oxidoreductase; Synthetic atpenin analogs

Indexed keywords

ATPENIN DERIVATIVE; FUNGICIDE; SUCCINATE DEHYDROGENASE (UBIQUINONE); UNCLASSIFIED DRUG;

AGRICULTURAL PROCEDURES; AGRICULTURAL SPECIES; ARTICLE; MITOCHONDRIAL RESPIRATION; SYNTHESIS;

ANIMALS; CATTLE; ELECTRON TRANSPORT COMPLEX II; ENZYME INHIBITORS; FUNGI; MITOCHONDRIA; OXIDATIVE PHOSPHORYLATION; PYRIDINES; PYRIDONES;

MAMMALIA;

EID: 76649092615     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.066     Document Type: Article

References (18)

1. Yankovskaya V., Horsefield R., Törnroth S., Luna-Chavez C., Miyoshi H., Léger C., Byrne B., Cecchini G., and Iwata S. Science 299 (2003) 700
2. Cecchini G., Schröder I., Gunsalus R.P., and Maklashina E. Biochim. Biophys. Acta 1553 (2002) 140
3. Miyadera H., Shiomi K., Ui H., Yamaguchi Y., Masuma R., Tomoda H., Miyoshi H., Osanai A., Kita K., and Ōmura S. Proc. Natl. Acad. Sci. U.S.A. 100 (2003) 473
4. Dickinson J.M., Hanson J.R., and Hitchcock P.B. J. Chem. Soc., Perkin Trans. 1 (1989) 1885
5. Kumagai H., Nishida H., Imamura N., Tomoda H., and Ōmura S. J. Antibiot. 43 (1990) 1553
6. Horsefield R., Yankovskaya V., Sexton G., Whittingham W., Shiomi K., Ōmura S., Byrne B., Cecchini G., and Iwata S. J. Biol. Chem. 281 (2006) 7309
7. Matsson M., and Hederstedt L. J. Bioenergetics Biomembranes 33 (2001) 99
8. Huang L., Sun G., Cobessi D., Wang A.C., Shen J.T., Tung E.Y., Anderson V.E., and Berry E.A. J. Biol. Chem. 281 (2006) 5965
9. Walter H. Z. Naturforsch. 63b (2008) 351
10. Yanase Y., Yoshikawa Y., Kishi J., and Katsuta H. In: Ohkawa H., Miyagawa H., and Lee P.W. (Eds). Pesticide Chemistry Ed(s): Crop Protection, Public Health and Environmental Safety (2007), Wiley-VCH, Weinheim 295-303
11. Ōmura S., Tomoda H., Kimura K., Zhen D.Z., Kumagai H., Igarashi K., Imamura N., Takahashi Y., Tanaka Y., and Iwai Y. J. Antibiot. 41 (1988) 1769
12. Rodgers P.B. Pestic. Sci. 27 (1989) 155
13. Trécourt F., Mallet M., Mongin O., and Quéguiner G. J. Org. Chem. 59 (1994) 6173
14. Trécourt F., Mallet M., Mongin O., and Quéguiner G. J. Heterocycl. Chem. 32 (1995) 1117
15. Quéguiner et al. reported that use of 2.2 equiv of n-butyl lithium gave optimum results, presumably due to chelation of an equivalent of base by the methoxy groups and ring nitrogen. However, we found that satisfactory product yields were obtained with 1.5 equiv of n-butyl lithium.
16. 5Cl: m/z calcd 309.704, m/z found 310.479 (M+); mp 210-211 °C.
17. The complex II assay was run in a 96-well microplate format using sub-mitochondrial membranes prepared from bovine heart or Septoria nodorum. The assay included 20 mM succinate as the electron donor and decyl ubiquinone as the electron acceptor. The reaction was initiated by addition of succinate and allowed to proceed for 10 min. Reduction of the dye 2,6-dichlorophenol-indophenol (DCIP) was monitored by absorbance at λ = 600 nm.
18. Investigating pro-forms of a much more active fungal SQR inhibitor such as 2e where there might be a higher possibility of attaining significant in vivo activity remains to be explored.