Quinoline-: Para -quinones and metals: Coordination-assisted formation of quinoline- ortho -quinones

Article abstract of DOI:10.1039/c7cc09478g

The reaction of the para-quinone 6,7-dichloroquinoline-5,8-dione with various transition metal dimers led to the unexpected formation of quinoline-ortho-quinone metal complexes. Systematic variation of the reaction conditions helped identify the solvent a

Full text of DOI:10.1039/c7cc09478g

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Quinoline-para-quinones and metals:
coordination-assisted formation
Cite this:DOI: 10.1039/c7cc09478g
of quinoline-ortho-quinones†
Received 11th December 2017,
Accepted 27th December 2017
Mario Kubanik,a Nelson Y. S. Lam,
Hannah U. Holtkamp,a Tilo Sohnel,
a
a
¨
Robert F. Anderson,ab Stephen M. F. Jamiesonb and Christian G. Hartinger
*
a
DOI: 10.1039/c7cc09478g
rsc.li/chemcomm
The reaction of the para-quinone 6,7-dichloroquinoline-5,8-dione of the electron transport chain in mitochondria, effectively
with various transition metal dimers led to the unexpected formation halting aerobic respiration and producing a semiquinone radical
of quinoline-ortho-quinone metal complexes. Systematic variation of in a redox reaction.8
the reaction conditions helped identify the solvent as the source of the
carbonyl oxygen.
The 5,8-quinolinedione derivative 6,7-dichloro-5,8-quinolinedione
(DQQ) was selected as the ligand and used to synthesize RuII-, OsII-,
IrIII- and RhIII-based metallopharmaceuticals. In order to prepare
Organometallic anticancer agents based on bioactive ligand DQQ, 8-hydroxyquinoline was oxidized using sodium chlorate in
systems have attracted a lot of attention due to their tuneable HCl (Fig. 1).10 The yield of this reaction after recrystallization was low
bioactivity against primary tumours or metastases and their (15–18%) which can be explained by the occurrence of several side
general versatility in drug development.1,2 Recently, we reported a reactions competing with the formation of the desired product, also
series of naphthoquinone complexes featuring an O,O-bidentate noted by Shen et al.11,12 The by-product 5,6,7-trichloro-2-alkoxy-8-
coordination motif where metal coordination induced the for- hydroxyquinoline (HHQCl) was isolated and characterized by NMR
mation of reactive oxygen species in cancer cells in dependence of spectroscopy, as was its methoxy derivative MeHQCl by single crystal
the nature of the metal centre.3,4 However, we found that these X-ray diffraction analysis (ESI†). The latter species surprisingly
compounds undergo ligand exchange reactions in the presence of formed during recrystallization with methanol. Due to the reduced
biological ligands which results to some extent in the cleavage of electron density of the 2-position of the pyridine ring proximal to
the ligand from the metal centre.3 In order to overcome this issue, the nitrogen, this position is amenable to oxidative nucleophilic
we turned our research efforts to N,O-chelating quinoline ligands, substitution resulting in the formation of compounds HQCl
which were found to form extremely stable and anticancer-active under the oxidative reaction conditions used.13
complexes.4,5 To combine the benefits of quinoline ligands
To improve the yield of DQQ and to minimize the side
with the interesting biological properties offered by quinone reactions occurring, methanol was replaced with ethanol,
structures, we aimed to explore the coordination chemistry and
biological activity of 5,8-quinolinediones. Moreover, a literature
search showed that only a few metal complexes of such ligands
have been reported.6,7
5,8-Quinolinedione derivatives are biologically active and
exhibit antitumor, antibacterial and antimalarial effects.8 This
structural motif is part of the pharmacophore found in several
antitumor antibiotics, such as streptonigrin and lavendamycin.9
The cytotoxicity of quinolinediones results from its inhibition
a School of Chemical Sciences, University of Auckland, Private Bag 92019,
Auckland 1142, New Zealand. E-mail: c.hartinger@auckland.ac.nz;
Web: http://hartinger.auckland.ac.nz
b Auckland Cancer Society Research Centre, University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand
Fig. 1 Preparation of DQQ, HQCl, and the ortho-quinoid metal com-
plexes 1–5. R = H (HHQCl), methyl (MeHQCl), ethyl (EtHQCl), n-propyl
(
† Electronic supplementary information (ESI) available. CCDC 1571650–1571654.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c7cc09478g
nPrHQCl), i-propyl (iPrHQCl), n-butyl (BuHQCl).
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Fig. 3 Molecular structure of one enantiomer of 1 drawn at 50% prob-
ability level. Solvent molecules were deleted for clarity. Selected bond
lengths are given in the ESI.†
The first coordination sphere is completed by chlorido and
p-cymene (1 and 2) or Cp* (4 and 5) ligands. The conversion
of DQQ to an ortho-quinone was confirmed by high resolution
ESI-MS indicating the absence of a chloro substituent after
complexation and substitution with an oxygen atom. The 1H NMR
Fig. 2 (top left) Time course of the conversion of DQQ to the methoxy
derivative in 25% H2O/methanol. (bottom) Time-dependent chromatograms
showing the growth of a second peak at lower retention time which was
identified by high resolution ESI-MS as the methoxy derivative (top right).
n-propanol, i-propanol and n-butanol in the recrystallization spectral shifts observed for the pyridine proton H2 were found
step. While the yields of DQQ did not improve, the ethyl, downfield for the Ru and Os complexes 1–3 as compared to DQQ,
n-propyl, i-propyl and n-butyl derivatives of 5,6,7-trichloro-2- whereas the Ir and Rh congeners showed a slight upfield shift for
alkoxy-8-hydroxyquinoline were isolated in up to 8% yield (ESI† the proton adjacent to the nitrogen atom.
¨
for 1H NMR spectra). Furthermore, HPLC analysis of DQQ
A similar reaction was observed by Corey and Konig who
dissolved in a mixture of MeOH/H2O revealed the conversion showed that anhydrides form from metal carboxylates, such as
of DQQ to 6- and 7-methoxy-5,8-quinolinedione derivatives by Cu(acetate)2, in the presence of DQQ,14 while in the presence of
replacing one of the chloro substituents with a methoxy group alcohols esters were obtained. In both cases a metal-coordinated
(Fig. 2). This is indicated by the presence of two peaks with close ortho-quinone formed. It was suggested that the addition of water
retention times and the same accurate mass as determined by to the intermediate yields a polymeric structure but elemental
HPLC-ESI-QToF-MS, indicating isomer formation. The chloro/ analysis data indicated the formation of a Cu(ortho-quinone)2
methoxy substitution reaction was found to be water content- complex,14 which we confirmed by ESI-MS ([M + Na]+ m/zexp
dependent. While the substitution was suppressed in pure water, 501.882, m/ztheor 501.879). These Cu(ortho-quinone)2 species may
acetonitrile and dichloromethane, it was completed within 32 h feature the same coordination mode as observed in 1–5 for the
in 25% H2O/methanol and even accelerated in a 1/1 mixture to formed ortho-quinone and the metal centres used. Using pseudo-
be complete in 10 h. In pure methanol, the reaction was to some octahedral organometallic moieties in our experiments where the
extent suppressed and only 50% conversion could be observed ligands cannot take part in the reaction, avoided the formation of
after 95 h.
As mentioned above, there are only a few 5,8-quinolinedione
polymers or higher metal-to-ligand ratio complexes.
To distinguish between the solvent or dissolved oxygen as
complexes known.6,7 In order to prepare complexes of the the source of the oxygen atom introduced in position 6 of the
general structure A (Fig. 1) from the 5,8-quinolinedione ligand ortho-quinone, we performed the reaction between DQQ and
DQQ, it was reacted with dimeric [M(L)Cl2]2 precursors (M = Ru, [M(L)Cl2]2 in dry protic and aprotic, deoxygenated solvents
Os, Rh, Ir; L = Z6-p-cymene [cym], Z6-biphenyl, Z5-pentamethylcyclo- and under different conditions, i.e., reflux, microwave-assisted
pentadienyl [Cp*]) in alcoholic solution under reflux for 1 h and at room temperature (Table 1). 1H NMR spectroscopy experi-
(Scheme 1), which resulted in the formation of purple precipi- ments with DQQ and [Ru(cym)Cl2]2 in CDCl3 showed neither
tates. While NMR spectroscopy suggested the formation of A, conversion of DQQ into the ortho-quinone nor complex formation,
X-ray diffraction analysis of single crystals of 1, 2, 4 and 5 even when refluxing the reaction mixture. Addition of MeOD to
surprisingly revealed the formation of the ortho-quinone complexes the mixture on the other hand led almost instantaneously to the
(Fig. 3; ESI†). All complexes featured the pseudo-tetrahedral formation of Ru compound 1. These studies demonstrate that
piano stool structure with the metal centre coordinated to the the ortho-quinone–metal complex only forms in the presence
pyridine nitrogen and the adjacent oxygen in a bidentate fashion. of protic solvents. As the use of dry degassed solvents had no
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Table 1 Reaction conditions used to study the formation of the ortho-
quinone during the reaction between DQQ and [Ru(cym)Cl2]2 in various
solvents
Table 2 50% inhibitory concentration (IC50) of 1–5 and DQQ in HCT116
human colorectal, NCI-H460 non-small cell lung and SiHa cervical
carcinoma cells
Solvent
Conditions
1a
IC50 valuesa/mM
Compound
HCT116
NCI-H460
SiHa
Methanol (abs), under N2
Reflux 1 h
M.W. 30 min, 80 1C
Reflux 1 h
M.W. 30 min, 80 1C
M.W. 30 min, 80 1C
M.W. 30 min, 80 1C
Reflux 1 h
M.W. 30 min, 80 1C
Reflux 1 h
Reflux 36 h
R.T. 5 d
M.W. 30 min, 80 1C
Reflux 21 h
R.T. 24 h
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
Yes
No
DQQ
3.7 Æ 0.8
3.7 Æ 0.6
15 Æ 2
Ethanol (abs), under N2
1
2
3
4
5
Z50
Z50
Z50
Isopropanol (abs), under N2
n-Butanol (abs), under N2
Water
1.8 Æ 0.7
3.9 Æ 0.8
4.4 Æ 0.6
Z30
Z30
Z30
Z30
440
Z30
440
Z30
440
THF (abs), under N2
a
SRB assay, 72 h incubation.
Acetonitrile (abs), under N2
Chloroform (abs), under N2
of the formed tetrahedral intermediate affords an oxonium ion,
to which the R–O bond is cleaved to yield the ortho-quinone–
metal complex in a metal coordination-assisted reaction and
RCl, as determined for the reaction with n-butanol by ESI-MS.
Having identified the solvent choice as essential for the for-
mation of the ortho-quinone from DQQ, the preparation of the
originally anticipated quinolinedione complexes was attempted by
using a silver salt to activate [Ru(cym)Cl2]2 in acetonitrile to form
Reflux 4 h
M.W. 30 min, 80 1C
Reflux 5 min
Reflux 4 h
Chloroform/methanol
DCM (abs), under N2
a
1 was detected by 1H NMR spectroscopy but not isolated. M.W.,
microwave.
influence on the reaction, the solvent should be the source of [Ru(cym)(CH3CN)2Cl]PF6. NMR spectroscopy and MS experiments
the oxygen atom in position 6 of the ortho-quinone. To further indicated the presence of the desired products in the reaction
verify this assumption, 18O-labelled water was used as a solvent mixture but we were not successful in isolating them. As the
in the reaction. Under these conditions, the formation of 1 was compounds were designed as anticancer agents with redox active
confirmed by ESI-MS. The mass spectrum featured a signal at ligand systems and this requires stability in aqueous solution,
m/z 507.9641 as the base peak. This ion was identified to this route was not further pursued, since in biological medium
contain three 18O atoms ([M + Na]+ m/ztheor 507.9648), which the DQQ complexes would be converted into ortho-quinone
is evidence that the protic solvents used were the source of compounds in situ. Instead, the ortho-quinone complexes 1–5
the oxygen atom. Performing the same reactions but with OsII, were evaluated on their cytotoxic properties. Surprisingly only the
RhIII and IrIII precursors supported this conclusion. This is also osmium complex showed promising activity in HCT116 human
in line with previous reports that other Lewis acids can be used colorectal, NCI-H460 non-small cell lung and SiHa cervical
in the derivatization of DQQ.15,16
carcinoma cells (Table 2) with IC50 values in the low mM range.
Based on these observations, the following mechanism for
The cytotoxicity of quinone-based compounds has been
the formation of ortho-quinones is suggested (Fig. 4): similar to suggested to be related to them undergoing redox reactions.8
Corey and Konig,14 the initial step involves coordination of the In order to study the impact of metal complexation on the redox
¨
metal centre to DQQ with DQQ acting as a bidentate ligand, properties of the ortho-quinone system, pulse radiolysis data
where the metal acts as a Lewis acid. The coordination of the was collected (Fig. 5 for 1). As the free ortho-quinone ligand of
metal centre activates C6 to a nucleophilic attack by ROH into 1–5 is not accessible, the redox properties of the complexes
the conjugated p-electron system. Subsequent decomposition were compared with that of DQQ. While the one-electron
reduction potential E(1) of DQQ is found in the positive range
at 96 mV, the metal complexes feature around À100 mV (ESI†),
which is similar to that of the anticancer drug candidate
KP1019 whose mode-of-action is based on the activation
by reduction mechanism.17 Compared to ortho- and para-
naphthoquinones the E(1) of DQQ is significantly higher, while
the E(1) of para-naphthoquinone is lower than that of the ortho
derivative.18 When comparing the para-quinone DQQ with the
complexes, where the ligand is present in an ortho-quinoid
structure, the difference in E(1) is significantly larger. This
indirectly demonstrates an impact of the metal centre on the
E(1) of the ligands, although no direct coordination occurs to
either of the oxygen atoms of the ortho-quinone. This can be
Fig. 4 Proposed reaction mechanism for the conversion of the quinoline-
explained by the conjugated electron system being present in
the ligands and involving the metal centre.
5,8-dione DQQ to an ortho-quinone derivative upon complexation to metal
centres in protic solvents.
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Analytical Services of the University of Auckland for access to
their facilities and Dr Dan Furkert (University of Auckland) for
useful discussions.
Conflicts of interest
There are no conflicts to declare.
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