Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6-trisubstituted benzimidazoles

Keng Yoon Yeong; Soo Choon Tan; Chun-Wai Mai; Chee-Onn Leong; Felicia Fei-Lei Chung; Yean Kee Lee; Chin Fei Chee; Noorsaadah Abdul Rahman

doi:10.1111/cbdd.13072

Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6-trisubstituted benzimidazoles

Chem Biol Drug Des. 2018 Jan;91(1):213-219. doi: 10.1111/cbdd.13072. Epub 2017 Aug 9.

Authors

Keng Yoon Yeong^{1

2}, Soo Choon Tan², Chun-Wai Mai³, Chee-Onn Leong^{3

4}, Felicia Fei-Lei Chung⁴, Yean Kee Lee⁵, Chin Fei Chee⁵, Noorsaadah Abdul Rahman⁵

Affiliations

¹ School of Science, Monash University Malaysia Campus, Bandar Sunway, Selangor, Malaysia.
² Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden, Penang, Malaysia.
³ School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
⁴ Center for Cancer and Stem Cell Research, International Medical University, Kuala Lumpur, Malaysia.
⁵ Department of Chemistry, University of Malaya, Kuala Lumpur, Malaysia.

PMID: 28719017
DOI: 10.1111/cbdd.13072

Abstract

Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD⁺ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP-1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results.

Keywords: anticancer; benzimidazole; molecular docking; nasopharyngeal; poly(ADP-ribose) polymerases; sirtuin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzimidazoles / chemistry*
Benzimidazoles / metabolism
Benzimidazoles / pharmacology
Binding Sites
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
Poly(ADP-ribose) Polymerase Inhibitors / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerases / chemistry*
Poly(ADP-ribose) Polymerases / metabolism
Sirtuin 1 / antagonists & inhibitors
Sirtuin 1 / metabolism
Sirtuin 2 / antagonists & inhibitors
Sirtuin 2 / metabolism
Sirtuins / antagonists & inhibitors*
Sirtuins / metabolism
Structure-Activity Relationship

Substances

Benzimidazoles
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
SIRT1 protein, human
SIRT2 protein, human
Sirtuin 1
Sirtuin 2
Sirtuins