PMID- 36830033
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230228
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 12
IP  - 2
DP  - 2023 Feb 13
TI  - Synthesis of New Shogaol Analogues as NRF2 Activators and Evaluation of Their 
      Anti-Inflammatory Activity, Modes of Action and Metabolic Stability.
LID - 10.3390/antiox12020475 [doi]
LID - 475
AB  - 6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber 
      officinale rhizomes. Many scientific studies have reported the diverse biological 
      activities of 6-shogaol. However, the major drawback of 6-shogaol is its 
      instability at room temperature. We synthesised new shogaol thiophene compounds 
      (STCs) by replacing the pentyl group in the sidechain with thiophene derivatives. 
      The STCs were tested for their nuclear factor erythroid 2-related factor 2 (NRF2) 
      activation ability in murine hepatoma cells (Hepa1c1c-7) by determining their 
      NAD(P)H quinone oxidoreductase 1 (NQO1) inducing ability and expression of 
      NRF2-associated antioxidant genes. The anti-inflammatory activity of STCs was 
      determined in Escherichia coli lipopolysaccharide (LPS(Ec))-stimulated 
      NR2-proficient and -silenced mouse microglial cells (BV-2) by measuring the 
      inflammatory markers, cytokines, and mediators. The modes of action (interacting 
      with the Kelch domain of KEAP1, covalent bonding with cysteines of KEAP1, and 
      inhibition of GSK-3beta enzyme activity) of NRF2 activation by STCs were determined 
      using commercially available kits. The in vitro metabolic stability of the STCs 
      in liver microsomes (humans, rats, and mice) was also investigated. The molecular 
      docking and molecular dynamics studies were conducted to identify the binding 
      poses, stability, and molecular interactions of the STCs in the binding pockets 
      of Kelch and BTB domains of KEAP1 and GSK-3beta enzyme. The new STCs were 
      synthesised in good yields of > 85%, with a purity of about 95%, using a novel 
      synthesis method by employing a reusable proline-proline dipeptide catalyst. The 
      STCs are more potent than 6-shogaol in activating NRF2 and reducing inflammation. 
      The nature of substituents on thiophene has a profound influence on the 
      bioactivity of the STCs. Phenylthiophene STC (STC5) is the most potent, while 
      thiophenes containing electron-withdrawing groups showed weaker bioactivity. The 
      bioactivity of 6-shogaol is in the micromolar range, whereas STC5 showed 
      bioactivity in the sub micromolar range. The STCs showed anti-inflammatory 
      effects via NRF2-dependent and NRF2-independent mechanisms. The STCs improved 
      NRF2 activity through multiple (KEAP1-independent and -dependent) mechanisms. The 
      STCs showed decreased reactivity with thiols than 6-shogaol and thus may possess 
      fewer side-effects than 6-shogaol. The STCs were more metabolically stable than 
      6-shogaol.
FAU - Mak, Kit-Kay
AU  - Mak KK
AUID- ORCID: 0000-0001-6939-5280
AD  - Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical 
      University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, 
      Selangor, Malaysia.
AD  - Centre of Excellence for Bioactive Molecules and Drug Delivery, Institute for 
      Research, Development & Innovation, International Medical University, 126, Jalan 
      Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Selangor, Malaysia.
AD  - School of Postgraduate Studies, International Medical University, 126, Jalan 
      Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Selangor, Malaysia.
FAU - Shiming, Zhang
AU  - Shiming Z
AD  - School of Postgraduate Studies, International Medical University, 126, Jalan 
      Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Selangor, Malaysia.
FAU - Sakirolla, Raghavendra
AU  - Sakirolla R
AD  - Department of Chemistry, Central University of Karnataka, Gulbarga 585367, 
      Karnataka, India.
FAU - Balijepalli, Madhu Katyayani
AU  - Balijepalli MK
AD  - Department of Pharmacology, Faculty of Medicine, Bioscience & Nursing, MAHSA 
      University, Jln SP 2, Bandar Saujana Putra, Jenjarom 42610, Selangor, Malaysia.
FAU - Dinkova-Kostova, Albena T
AU  - Dinkova-Kostova AT
AUID- ORCID: 0000-0003-0316-9859
AD  - Division of Cellular Medicine, School of Medicine, Jacqui Wood Cancer Centre, 
      University of Dundee, Dundee DD1 4HN, UK.
AD  - Departments of Medicine and Pharmacology and Molecular Sciences, School of 
      Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
FAU - Epemolu, Ola
AU  - Epemolu O
AD  - Principal Research Scientist-In Vitro/In Vivo DMPK, Charles River Laboratories 
      Edinburgh Ltd., Tranent EH33 2NE, UK.
FAU - Mohd, Zulkefeli
AU  - Mohd Z
AUID- ORCID: 0000-0001-9852-7238
AD  - Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical 
      University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, 
      Selangor, Malaysia.
AD  - Centre of Excellence for Bioactive Molecules and Drug Delivery, Institute for 
      Research, Development & Innovation, International Medical University, 126, Jalan 
      Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Selangor, Malaysia.
FAU - Pichika, Mallikarjuna Rao
AU  - Pichika MR
AD  - Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical 
      University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, 
      Selangor, Malaysia.
AD  - Centre of Excellence for Bioactive Molecules and Drug Delivery, Institute for 
      Research, Development & Innovation, International Medical University, 126, Jalan 
      Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Selangor, Malaysia.
LA  - eng
GR  - FRGS/1/2018/WAB13/MAHSA/02/1/Ministry of Higher Education/
GR  - PMHS I-2018 (02)/International Medical University, Malaysia/
PT  - Journal Article
DEP - 20230213
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC9951879
OTO - NOTNLM
OT  - 6-shogaol
OT  - NRF2
OT  - Zingiber officinale
OT  - anti-inflammatory activity
OT  - microsomal stability
OT  - molecular docking
OT  - thiophene derivatives
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/26 06:00
MHDA- 2023/02/26 06:01
PMCR- 2023/02/13
CRDT- 2023/02/25 01:11
PHST- 2023/01/18 00:00 [received]
PHST- 2023/02/03 00:00 [revised]
PHST- 2023/02/06 00:00 [accepted]
PHST- 2023/02/25 01:11 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/02/26 06:01 [medline]
PHST- 2023/02/13 00:00 [pmc-release]
AID - antiox12020475 [pii]
AID - antioxidants-12-00475 [pii]
AID - 10.3390/antiox12020475 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2023 Feb 13;12(2):475. doi: 10.3390/antiox12020475.