TY - JOUR
T1 - Unprecedented formation of palladium(II)-pyrazole based thiourea from chromone thiosemicarbazone and [PdCl2(PPh3)2]
T2 - Interaction with biomolecules and apoptosis through mitochondrial signaling pathway
AU - Haribabu, Jebiti
AU - Balachandran, Chandrasekar
AU - Tamizh, Manoharan Muthu
AU - Arun, Yuvaraj
AU - Bhuvanesh, Nattamai S.P.
AU - Aoki, Shin
AU - Karvembu, Ramasamy
N1 - Funding Information:
We have accomplished the synthesis and characterization of novel palladium(II) complexes with pyrazole appended thiourea ligands. For the first time, conversion of chromone thiosemicarbazone to pyrazole based thiourea was noted. The reaction mechanism was studied by mass and 1 H NMR spectroscopic methods. The distorted square planar structure of the complexes was determined using XRD technique. The DNA interaction ability of the compounds has been demonstrated using physicochemical methods which revealed that the compounds can bind with DNA via intercalation. The DNA binding of the complexes was influenced by the substituent at the terminal nitrogen of the thiosemicarbazone ligand, which was supported by molecular docking studies. The results from molecular docking studies validated the biomolecular interactions of the complexes. The results of agarose gel electrophoresis revealed that complex 2 can effectively promote cleavage of plasmid DNA. In vitro cytotoxic activity of the complexes was investigated against A549 (lung cancer), HepG-2 (liver carcinoma), U937 (lymphoma) and IMR90 (lung normal) cells, and compared to that of cisplatin, doxorubicin and daunorubicin, the well-known anticancer agents. Complex 2 was the most active against HepG-2 cells, which was twofold superior to cisplatin. The complexes showed moderate cytotoxic activity towards A549 and U937 cells. The cell death mechanism of the active complex ( 2 ) was found to be apoptosis as assessed by flow cytometry and confocal microscopic studies. Complex 2 induced cell cycle arrest at G1 phase. The apoptosis was induced by complex 2 via mitochondrial mediated pathway which was confirmed by Western blot analysis, and possible apoptosis cell death mechanism was proposed. Complex 2 exhibited appreciable binding efficacy with biomolecules and possessed potent anticancer activity. In vivo experiments will be carried out for this active complex to establish its potential as clinical drug.
Funding Information:
J. H. thanks the Japan Society for the Promotion of Science (JSPS) for the fellowship (P18412). R. K. thanks SERB for the financial support.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/4
Y1 - 2020/4
N2 - Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.
AB - Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.
KW - Apoptosis
KW - Biomolecules
KW - Cytotoxicity
KW - Michael addition
KW - Mitochondrial signaling pathway
KW - Palladium(II)
UR - http://www.scopus.com/inward/record.url?scp=85078507319&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2019.110988
DO - 10.1016/j.jinorgbio.2019.110988
M3 - Article
C2 - 31981770
AN - SCOPUS:85078507319
SN - 0162-0134
VL - 205
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
M1 - 110988
ER -