title: Identification of Michael acceptor-centric pharmacophores with substituents that yield strong thioredoxin reductase inhibitory character correlated to antiproliferative activity.
abstract: OBJECTIVE
  The role of thioredoxin reductase (TrxR) in tumorigenesis has made it an attractive anticancer target. A systematic approach for development of novel compounds as TrxR inhibitors is currently lacking. Structurally diversified TrxR inhibitors share in common electrophilic propensities for the sulfhydryl groups, among which include the Michael reaction acceptors containing an α,β-unsaturated carbonyl moiety. We aimed to identify features among structurally diversified Michael acceptor-based compounds that would yield a strong TrxR inhibitory character.
  
  
  RESULTS
  Structurally dissimilar Michael acceptor-based natural compounds such as isobutylamides, zerumbone, and shogaols (SGs) were found to possess a poor TrxR inhibitory activity, indicating that a sole Michael acceptor moiety was insufficient to produce TrxR inhibition. The 1,7-diphenyl-hept-3-en-5-one pharmacophore in 3-phenyl-3-SG, a novel SG analog that possessed comparable TrxR inhibitory and antiproliferative potencies as 6-SG, was modified to yield 1,5-diphenyl-pent-1-en-3-one (DPPen) and 1,3-diphenyl-pro-1-en-3-one (DPPro, also known as chalcone) pharmacophores. These Michael acceptor-centric pharmacophores, when substituted with the hydroxyl and fluorine groups, gave rise to analogs displaying a TrxR inhibitory character positively correlated to their antiproliferative potencies. Lead analogs 2,2'-diOH-5,5'-diF-DPPen and 2-OH-5-F-DPPro yielded a half-maximal TrxR inhibitory concentration of 9.1 and 10.5 μM, respectively, after 1-h incubation with recombinant rat TrxR, with the C-terminal selenocysteine residue found to be targeted.
  
  
  METHODS
  Identification of Michael acceptor-centric pharmacophores among diversified compounds demonstrates that a systematic approach to discover and develop Michael acceptor-based TrxR inhibitors is feasible.
  
  
  CONCLUSIONS
  A strong TrxR inhibitory character correlated to the antiproliferative potency is attributed to structural features that include an α,β-unsaturated carbonyl moiety centered in a DPPen or DPPro pharmacophore bearing hydroxyl and fluorine substitutions.
authors: Department of Pharmacy, National University of Singapore , Singapore, Republic of Singapore .
authors: Fei-Fei
authors: FF
authors: Gan
authors: Kamila K
authors: KK
authors: Kaminska
authors: Hong
authors: H
authors: Yang
authors: Chin-Yee
authors: CY
authors: Liew
authors: Pay-Chin
authors: PC
authors: Leow
authors: Choon-Leng
authors: CL
authors: So
authors: Lan N L
authors: LN
authors: Tu
authors: Amrita
authors: A
authors: Roy
authors: Chun-Wei
authors: CW
authors: Yap
authors: Tse-Siang
authors: TS
authors: Kang
authors: Wai-Keung
authors: WK
authors: Chui
authors: Eng-Hui
authors: EH
authors: Chew
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002599:Chalcone; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase