2. Academic Validation
  3. Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

  • Eur J Med Chem. 2017 Mar 31:129:287-302. doi: 10.1016/j.ejmech.2017.02.017.
Stefano Sainas 1,  Agnese C Pippione 1,  Marta Giorgis 1,  Elisa Lupino 2,  Parveen Goyal 3,  Cristina Ramondetti 2,  Barbara Buccinnà 2,  Marco Piccinini 2,  Rodolpho C Braga 4,  Carolina H Andrade 4,  Mikael Andersson 3,  Ann-Christin Moritzer 5,  Rosmarie Friemann 6,  Stefano Mensa 7,  Salam Al-Kadaraghi 8,  Donatella Boschi 1,  Marco L Lolli 9
Affiliations

Affiliations

  • 1 Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy.
  • 2 Department of Oncology, University of Torino, via Michelangelo 27/B, 10126 Torino, Italy.
  • 3 Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg Sweden.
  • 4 LabMol, Faculty of Pharmacy, Federal University of Goias, 74605-170 Goiania, Brazil.
  • 5 Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg Sweden; Department of Chemistry, Biochemistry, University of Bielefeld, Universitätsstraße 25, 33615 Bielefeld, Germany.
  • 6 Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg Sweden; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive West Stanford, CA 94305-5126, USA.
  • 7 Stephenson Institute for Renewable Energy, Department of Chemistry, University of Liverpool, L69 7ZF Liverpool, UK.
  • 8 Department of Biochemistry and Structural Biology, Lund University, Sweden.
  • 9 Department of Science and Drug Technology, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy. Electronic address: marco.lolli@unito.it.
PMID: 28235702 DOI: 10.1016/j.ejmech.2017.02.017
Abstract

A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.

Keywords

Autoimmune diseases; Bioisosterism; Brequinar; Dihydroorotate dehydrogenase (DHODH) inhibitors; Leflunomide; X-ray-crystallography.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z