Theralase Technologies Inc. V.TLT

Liver Cancer Research

[99942Apophis]

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A bis-indazolic ruthenium(II) complex: Reactivity and biological studies on cancer cells

Author links open overlay panelDanilo K.S.SalesaLlian M.T.SimplcioaCarlos D.S.da SilvabCarolina M.B.EnjubVanessa B.SilvabTrcio de F.PaulocIvanilson P.SantosdHelenita C.QuadrosdCssio S.MeiradMilena B.P.SoaresdeLuiz G. de F.LopescEduardo H.S.de SousacDenise S.de Sb

Highlights

 

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Metal complexes exhibited anticancer activity against different tumor cell lines.

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Suitable induction and selective cytotoxicity to cancer cell lines.

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DNA fragmentation is a biological effect of the metal complex in HepG2 cells.

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Cell death promoted by the bis-indazolic metal complex caused by apoptosis in HepG2 cells.

 

Abstract

Ru(II)-based complexes have been widely investigated as potential anticancer agents, leading cell death of tumor mass. In this work, a metal complex, cis-[RuII(Hind)2(bpy)2](PF6)2 (Hind = indazole and bpy = 2,2′-bipyridine), was synthesized and characterized by elemental analysis, spectroscopy and electrochemistry methods, validating its formulation. This complex can act as a Brnsted-Lowry acid with pKa close to physiological pH. Photosubstitution reaction was noticed upon blue light irradiation with release of indazol molecules in acetonitrile, a behavior also noticed, indicating its photosensitivity. This metal complex was screened in vitro against distinct human cancer cell lines. Hepatocellular carcinoma cells (HepG2) were the most sensitive, with the half maximal inhibitory concentration (IC50) at 7.2 µmol L−1. Further biological studies showed DNA fragmentation induced by this compound, which resulted in cell cycle arrest in S phase and HepG2 cell death by apoptosis. Moreover, there was no significant cytotoxicity against healthy human pulmonary fibroblast cells (MRC-5), and therefore the compound exhibited a high selectivity index, indeed a better in vitro anticancer profile than some structurally related compounds (e.g. NAMI-A and KP1039). Our results indicate exciting potential pharmacological applications of this metal complex in liver cancer treatment, which might be supported by further studies.

Graphical abstract

A new KP1339 analogue ruthenium complex, cis-[Ru(Hind)2(bpy)2](PF6)2, showed expressive cytotoxicity against liver cancer cells, HepG2, causing DNA fragmentation, interrupting the cell cycle in phase S and resulting in cell death by apoptosis.

 

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Abbreviations

B16-F10

murine melanoma

bpy

2,2′-bipyridine

CDDP

cisplatin

COSY

homonuclear correlation spectroscopy

DFT

density functional theory

DMF

dimethylformamide

DMSO

dimethyl sulfoxide

DMSOd6

deutered dimethyl sulfoxide

DNA

deoxyribonucleic acid

Egap

electronic gap

Fc

ferrocene

FOR000

cis-[RuCl2(bpy)2]

FOR002

cis-[RuCl(indazole)(bpy)2]PF6

FOR0D2

cis-[Ru(indazole)2(bpy)2](PF6)2

HCT116

human colon carcinoma

HepG2

hepatocellular carcinoma cells

Him

imidazole

Hind

indazole

HOMO

highest occupied molecular orbital

IC50

inhibitory concentration 50%

IL

intraligand

INCA

National Cancer Institute of Brazil

KP1019

(H2ind)[trans-RuCl4(Hind)2]

KP1339

Na[trans-RuCl4(Hind)2]

LED

light emitting diode

LLCT

ligand-to-ligand charge transfer

LUMO

lowest unoccupied molecular orbital

MLCT

metal-to-ligand charge transfer

MRC-5

pulmonary fibroblast cells

NAMI-A

(H2im)[trans-RuCl4(S-DMSO)(Him)]

PTBA

tetrabutylammonium perchlorate

SI

selectivity index

TACE

transarterial chemoembolization

TD-DFT

time-dependent density functional theory

TLD 1443

[Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′′′-terthiophene)-imidazo[4,5-f][1,10]phenanthroline)]2+

λmax

band of electronic absorption spectroscopy

[tamarindo1]

Ruthenium as used in the chemical industry and as a synthesis in various organic chemicals in the pharmaceutical industry, in addition its replacement of mercury in various membrane technologies is creating a growing demand for this extremely rare metal compound causing a high CAGR. I did not know this. 

[Johnandrose22]

Now we’re discussing the possible use of TLT compounds to combat liver cancer...remarkable...while the company that owns these compounds is valued at @ $.20....remarkable.

[robertshaw]

Blowjobjoe's bosses short us every f?cking day, also remarkable.

[Jaro1977]

robertshaw, I was not around 6-7 years ago.  How is this "joe" and who are his bossess? Thanks

[Jaro1977]

robertshaw, I meant who is "joe"? Thanks,

[robertshaw]

Blowjobjoe is a guy same as southtiertom, who got paid 50 cents Per post by his boss (anonymous1), to bash this technology and praise the idiot (former CEO rogers dumbling White for his stupid decisions made in the past 6 years ).

[robertshaw]

All the royal long shareholders know Blowjobjoe worked 24x7... He was sued by RDW in Ontario's Court, and quit spreading rumors thereafter

[Jaro1977]

thanks for your reply.  I understand now.