Targeting protein kinase and DNA molecules by diimine–phthalate complexes in antiproliferative activity
Authors: Vinod Devaraji
Narayanaperumal Pravin
Natarajan Raman
Journal: International Journal of Biological Macromolecules (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Anticancer activity; Metallointercalators; Molecular docking.
Affiliations: Research Department of Chemistry, VHNSN College, Virudhunagar 626001, India. Electronic address: ., College of Pharmacy, Madras Medical College, Chennai 600003, India.

Abstract:  The serendipitous discovery of the anticancer drug cisplatin cemented medicinal inorganic chemistry as an independent discipline in 1960s. DNA and protein kinases are one of the major intracellular targets of many anticancer drugs. It is thus highly desirable to develop metal complexes, either by interacting with DNA or to target alternative cellular machinery such as protein kinases to provide a more effective means of monitoring disease progression. In this study we report the synthesis and characterization of few novel Cu(II) and Zn(II) Knoevenagel condensed metallointercalators incorporating phthalic acid. The intercalation behavior of the complexes with DNA is confirmed by spectral and analytical experiments. Due to the promising performance of DNA interaction efficacy of Cu(II) complexes 1-4, their in vitro and in vivo anticancer properties are explored on various cancerous cell lines which reveal that they exhibit substantial anticancer activity without affecting the normal cells. It is found that the complex 1 induces apoptosis in Hep G2 cells. Theoretically, DFT is used to optimize the Cu(II) complexes 1-4 to explore their quantum mechanical properties and to carry out affinity studies against cyclin dependant kinase 2 (CDK2) to understand atomic level interactions. Further, the complex-receptor stability is confirmed by molecular dynamics. 

Retracted: No

PubPeer comments:
 Could the authors comment on what appear to be some repeated features? ![file] , 
 #1 Another version: [Pravin Raman (2014)] , at right. ![file] , 
 Fig. 6.  Agarose gel electrophoresis pattern for the cleavage of pBR322 plasmid DNA (10 M) by complexes 1u20138 at 37 u25e6C after incubation for 45 min at 25 M concentration with histogram of % cleavage forms; lane 1: DNA control; lane 2: (100 M) CuCl2 + DNA; lane 3: (100 M) ZnCl2 + DNA; lane 4: complex 1 + DNA; lane 5: complex 2 + DNA; lane 6: complex 3 + DNA. Lane 7: complex 4 + DNA; lane 8: complex 5 + DNA; lane 9: complex 6 + DNA; lane 10: complex 7 + DNA; lane 11: complex 8 + DNA. ![file] Fig. 6 from [Pravin Raman (2014)] .  Agarose gel electrophoresis pattern for the cleavage of pBR322 plasmid DNA (10 mM) by complexes 1-8 at 37 u0004C after incubation for 45 min at 30 mM concentration with histogram of % cleavage forms. lane 1: DNA control; lane 2: (100 mM) CuCl2 + DNA; lane 3: (100 mM) ZnCl2 + DNA; lane 4: complex 1 + DNA; lane 5: complex 2 + DNA; lane 6: complex 3 + DNA. lane 7: complex 4 + DNA; lane 8: complex 5 + DNA; lane 9: complex 6 + DNA; lane 10: complex 7 + DNA; lane 11: complex 8 + DNA. ![file] Fig. 7.  Agarose gel electrophoresis pattern for the cleavage pattern of pBR322 DNA (10 M) by complexes 1 and 5 at 37 u25e6C after incubation for 45 min (25 M) concentration with histogram of % cleavage forms. In absence and presence of complex 1 with different activators: lane 1, DNA control; lane 2, DNA+Asc (100 M); lane 3, DNA+ H2O2 (100 M); lane 4, DNA+ GSH (100 M); lane 5, DNA+ MPA (100 M); lane 6, DNA+ 1 +Asc (100 M); lane 7, DNA+ 1 + MPA (100 M); lane 8, DNA+ 1 + GSH (100 M); lane 9, DNA+ 1 + H2O2 (100 M); lane 10, DNA+ 5 + GSH (100 M); lane 11, DNA+ 5 + H2O2 (100 M); lane 12, DNA+ 5 + MPA (100 M); lane 13, DNA+ 5 +AH2 (100 M). ![file] Fig. 7 from Pravin Raman (2014).  Agarose gel electrophoresis pattern for the cleavage pattern of pBR322 DNA (10 mM) by complexes 1 and 5 at 37 u0004C after incubation for 45 min 30 mM concentration with histogram of % cleavage forms. In absence and presence of complex 1 with different activators: lane 1, DNA control; lane 2, DNA + Asc (100 mM); lane 3, DNA + H2O2 (100 mM); lane 4, DNA + GSH (100 mM); lane 5, DNA u00fe MPA (100 mM); lane 6, DNA + 1 + Asc (100 mM); lane 7, DNA + 1 + MPA (100 mM); lane 8, DNA + 1 + GSH (100 mM); lane 9, DNA + 1 + H2O2 (100 mM); lane 10, DNA + 5 + GSH (100 mM); lane 11, DNA + 5 + H2O2 (100 mM); lane 12, DNA + 5 + MPA (100 mM); lane 13, DNA + 5 + AH2 (100 mM). ![file] , 
 Fig. 11.  Hoechst 33258 staining of HepG2 liver cancer cells for 24 h....(b) treated with 10 M and 20 M ... of complex 1 . ![file] (a) and (c) are left as exercises for the reader. ,