title: Novel amino acid derivatives bearing thieno[2,3-d]pyrimidine moiety down regulate NF-κB in γ-irradiation mediated rat liver injury.
abstract: A series of different amino acid-bearing thieno[2,3-d]pyrimidine moiety was synthesized via green chemistry aspects incorporating water as a solvent to give 2a-f, which were then acidified to attain the target compounds 3-9. Moreover, a tricyclic imidazothienopyrimidine of the glycine derivative (3) was synthesized to give (10). The title compounds were characterized by FT-IR, Mass,13C-1HNMR spectroscopy and microanalysis. All the obtained amino acid-derivatives were screened for their post-irradiation protective efficacy in young rats. γ-Irradiation exposure was employed to induce oxidative stress. Radiation triggered significant alterations in the hematologic and blood - biochemical parameters. Further, a significant deterioration of hepatic antioxidant status was observed. Furthermore, a significant elevation of Nuclear Factor-kappa B (NF-κB) protein expression and level, which induced elevation in Cyclooxygenase-2 (COX-2) activity and cytochrome P450 2E1 (CYP2E1) gene expression were detected in hepatic tissues. Additionally, elevated levels of Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) were perceived in serum of γ-irradiated young rats. However, most of the newly synthesized derivatives showed significant protective effects against injuries induced by γ-irradiation exposure, via ameliorating the altered hematopoietic system and activity of different biochemical parameters in blood. The results indicate that the antioxidant and anti-inflammatory mechanism of these compounds could be attributed to the significant down-regulation NF-κB protein expression in hepatic tissues. Subsequently, NF-κB could regulate TNF-α and IL-6 levels, COX-2 activity and CYP2E1 gene expression. Methionine derivative 8 was found to be the most active one.
  
  
  CONCLUSIONS
  These new amino acid-derivatives showed promising outcomes as curative agents against γ-irradiation induced oxidative stress and physiological disturbance in different organs of young animals. Beyond, they may represent a novel selective class for treating liver injury induced by γ-irradiation in young rats, via down-regulation of NF-κB expression. Further investigations are warranted prior to the clinical use of these new compounds.
authors.affiliation: Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Nasr City, Cairo, Egypt. Electronic address: nashwazah@hotmail.com.
authors.forename: Nashwa H
authors.initials: NH
authors.lastname: Zaher
authors.affiliation: Regional Center for Food and Feed (RCFF), Agriculture Research Center, Giza, Egypt.
authors.forename: Asmaa A M
authors.initials: AA
authors.lastname: Salem
authors.affiliation: Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Nasr City, Cairo, Egypt.
authors.forename: Amel F M
authors.initials: AF
authors.lastname: Ismail
mesh_terms: D000596:Amino Acids / Q000627:therapeutic use*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005720:Gamma Rays / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
chemical_list: D000596:Amino Acids; D016328:NF-kappa B; D011743:Pyrimidines
keywords: Amino acids; Cyclooxygenase-2; Cytochrome P 450 2E1 (CYP2E1); Nuclear Factor kappa B; Thieno[2,3-d]pyrimidines; γ-Irradiation