Expanding the Arsenal of PtIV Anticancer Agents: Multi-action PtIV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group

Article abstract of DOI:10.1002/anie.201910014

Most multi-action Pt^IV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of Pt^IV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt^IV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO₂, rapidly generating the active drugs. In contrast, succinate-linked drugs did not readily release the free drugs. The carbonate-bridged ctc-[Pt(NH₃)₂(PhB)(Gem-Carb)Cl₂] was significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH₃)₂(PhB)(Gem-Suc)Cl₂], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine.

Full text of DOI:10.1002/anie.201910014

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Expanding the Arsenal of PtIV Anticancer Agents; Multi-action
PtIV Anticancer Agents with Bioactive Ligands Possessing
Hydroxyl Functional Group
Authors: Dan Gibson, Thirumal Yempala, Tomer Babu, Subhendu
Karmakar, Alina Nemirovski, Maisaloon Ishan, and Valentina
Gandin
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910014
Angew. Chem. 10.1002/ange.201910014
Link to VoR: http://dx.doi.org/10.1002/anie.201910014
http://dx.doi.org/10.1002/ange.201910014

10.1002/anie.201910014
Angewandte Chemie International Edition
Expanding the Arsenal of PtIV Anticancer Agents; Multi-action PtIV
Anticancer Agents with Bioactive Ligands Possessing Hydroxyl Functional
Group.
Thirumal Yempala,a‡ Tomer Babu,a‡ Subhendu Karmakar,a‡ Alina Nemirovski,a Maisaloon
Ishan,a Valentina Gandin,b and Dan Gibsona*
a Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem,
Jerusalem-9112102, Israel.
b Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131
Padova, Italy.
‡These authors contributed equally to this work
*Corresponding author E-mail: dang@ekmd.huji.ac.il
Dedicated to the late Prof. J. Katzhendler for his mentorship, inspiration and friendship.
1
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10.1002/anie.201910014
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Abstract
Most multi-action PtIV prodrugs have bioactive ligands containing carboxylates. This is
probably due to the ease of carboxylating the OH axial ligands and because following reduction,
the active form of the agent is released. A major challenge is to expand the arsenal of bioactive
ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV
prodrugs that release in their native form, molecules with OH groups. We linked the OH groups
of gemcitabine (Gem), paclitaxel, and estramustine (EM) to the PtIV derivative of cisplatin by a
carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active
drugs. In contrast, succinate linked drugs did not readily release the free drugs. The carbonate
bridged ctc-[Pt(NH3)2(PhB)(Gem-Carb)Cl2] was significantly more cytotoxic than the succinate
bridged ctc-[Pt(NH3)2(PhB)(Gem-Suc)Cl2]. In vivo data show that carbonate-bridged compound
was more potent and less toxic than gemcitabine, cisplatin and co-administration pf cisplatin and
gemcitabine.
2
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10.1002/anie.201910014
Angewandte Chemie International Edition
Despite advances in the treatment of cancer, square planar PtII complexes such as cisplatin,
carboplatin and oxaliplatin (Figure 1) are widely used to treat several forms of cancer, alone or in
combination with other drugs.1,2 They are administered intravenously and after entering the cancer
cell, the cis-[Pt(Am)2]2+ binds to two adjacent guanines on the same DNA strand, distorting its
structure and triggering cellular responses that result in apoptosis.3,4 Pt drugs suffer from two major
problems: the ability of the tumors to acquire resistance to the drugs and dose-limiting side
effects.5,6,7 To overcome resistance to a given drug, and diminish side effects, clinicians treat
patients with a combination of drugs that have different cellular targets and different modes of
action.8,9,10
Octahedral multi-action PtIV complexes are used as prodrugs to overcome resistance.11 They
are usually prepared by oxidizing the square planar PtII drugs with H2O2 and subsequent
modification of the axial hydroxido ligands. PtIV complexes are particularity suitable as prodrugs
because they are stable outside the cancer cell and activated by reduction inside the cell. The
reduction severs the bonds between the platinum and the axial ligands, regenerating the original
PtII drug and releasing the two axial ligands (Figure 1). The axial ligands of PtIV complexes can be
utilized as: lipophilic moieties that enhance passive cellular uptake; tumor targeting agents; or
linkers to polymers, nanoparticles, proteins or other delivery agents.12,13,14 In addition, they can be
bioactive agents such as approved drugs, enzyme inhibitors, pathway activators or suppressors,
epigenetic modifiers, antimetabolites etc. that attack different cellular targets and work in synergy
with PtII drugs to overcome resistance.15,16,17
Figure 1 – (top row)-the FDA approved PtII drugs: cisplatin, carboplatin and oxaliplatin. and
dual-action (A) and triple-action (B) PtIV prodrugs. (middle row)- synthesis and mode of action of
PtIV prodrugs and four anticancer drugs with no carboxylates (bottom row).
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10.1002/anie.201910014
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The nature of the linkage between the ligand and the axial hydroxido of PtIV (carboxylate,
carbamate, ether or carbonate) is not usually important when conjugating PtIV to lipophilic
moieties, targeting agents or delivery systems. In contrast, it is important for multi-action PtIV
prodrugs that should release the bioactive moieties from the axial positions, in their active form.
This implies that the axial oxygen (Pt-OR) should be an integral part of the bioactive molecule, or
be part of a linker that can readily release the active drug. Most multi-action PtIV prodrugs, have
bioactive moieties possessing a carboxyl group (Figure 1 A, B), probably because following
reduction, the active form of the agent is released.
Drugs such as taxol, doxorubicin, 5-fluoruracil, gemcitabine, topotecan or irinotecan are given
in combination with platinum drugs in the clinic.18,19,20 They have no carboxylates, but have either
hydroxy or amine groups (Figure 1 – bottom row).
Therefore, a major challenge is the synthesis of multi-action PtIV complexes with FDA
approved drugs that have no carboxylates. Attempts were made to conjugate OH bearing bioactive
molecules to PtIV. Since no effective protocols exist for direct conjugation of OH bearing moecules
to the axial positions of PtIV, ester or ether linkers were used to conjugate estrogens,21
combretastatin- A4,22 7-hydroxy coumarin or wagonin23, NBDHEX,24 etc to PtIV (Figure 2). Due
to the relative stabilities of the ether and ester bonds, the active moieties are not released rapidly
following reduction.
Figure 2 – PtIV prodrugs to which OH containing bioactive ligands were attach by forming
an ester link to the OH (A & E) or via an ether linkage (B, C, D & F)
We developed a new conceptual approach to attain this goal. It is based on reports that
carbonic acid monoesters are unstable and decompose to alcohols and CO2.25 If we form a
carbonate bridge linking the axial OH of PtIV and the OH of the bioactive moiety, reduction of
the PtIV will generate an unstable carbonic acid monoester that will rapidly release the active
moiety.
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10.1002/anie.201910014
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Figure 3 – The synthetic route for conjugating the OH group of a ligand to the axial position
of PtIV via a carbonate linkage (top); the release and activation of the bioactive ligand (middle);
and the three PtIV multi-action prodrugs with gemcitabine, taxol and estramustine.
To test our hypothesis, we synthesized three PtIV derivatives of cisplatin with carbonate
bridging the platinum and OH groups of the drugs. The synthetic strategy appears in Figure 3.
The OH group of the ligand is activated with DSC, [bis(2,5-dioxopyrrolidin-1-yl)carbonate], and
then reacted with the axial OH of the PtIV to form the carbonate link. To the best of our
knowledge, there are very few reports on PtIV complexes with carbonate axial ligands, and no
description of this synthetic approach.26 We chose three anticancer drugs that have cellular
targets different from cisplatin: gemcitabine (Gem); an antimetabolite,27 Paclitaxel (Taxol); acts
on the tubulin-microtubule system28 and estramustine (EM); acts on the tubulin-microtubule
system and on the DNA (Figure 3).
The synthesis is described in in Figure 3. Detailed procedures are provided in the
supplementary material. All compounds were purified by preparative HPLC and characterized by
195Pt and 1H NMR, and ESI-MS. Purity was verified by elemental analysis.
To test whether the reduction of the carbonate linked molecules leads to the release of the
drugs, we exposed ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2], ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] and
ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2] to an excess of ascorbic acid at 37°C in phosphate buffer
(pH=7.0) and monitored the reduction by HPLC. The reduction of ctc-[Pt(NH3)2(Tax-
Carb)(OH)Cl2] was monitored by 1H NMR.
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10.1002/anie.201910014
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Figure 4 – A) HPLC chromatograms of ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] – top, Gem
(middle) and the reaction mixture of ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] with 10 eq of ascorbate
after 2 h. B) 1H NMR spectra of the reduction of ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] with 5 eq of
ascorbate, monitoring the amide proton of taxol.
After 2 h, the peak of ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] vanished, and a new peak with the
same retention time and the same ESI-MS as Gem appears, indicating complete reduction of ctc-
[Pt(NH3)2(Gem-Carb)(PhB)Cl2] and full release of Gem (Figure 4A). The HPLC data for the
reduction of ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] with 20 eq of ascorbate is depicted in Figure S35.
We incubated ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] with 5 eq of ascorbate and the reduction was
followed by 1H NMR. The NH proton in ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] resonates at ~ 9.2 ppm
and in free taxol at ~ 8.85 ppm. The reduction of ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] with the
concurrent growth of Taxol is depicted in Figure 4B with a half-life of 25 min. No intermediates
were observed, confirming rapid decarboxylation. Similar results were obtained for the reduction
of ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2] (Figure 5A).
OH containing bioactive molecules can be conjugated to PtIV prodrugs via a succinate
bridge (Figure 3A, 3E). Following reduction, the succinated-drug is released. To obtain the free
drug, the ester bond to the succinate has to be severed by hydrolysis or by esterases. We prepared
ctc-[Pt(NH3)2(Gem-Suc)(PhB)Cl2] and ctc-[Pt(NH3)2(EM-Suc)(OAc)Cl2], the PtIV succinate-
linked analogs of ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] and ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2]
and monitored their reduction, and the release of Gem-Suc (Figure S36) or EM-Suc by HPLC
(Figure 5B).
One hour after reduction of ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2] began, free EM is observed,
and after 8 h reduction was nearly complete with concurrent release of EM ( RT=28.1 min. -Figure
5A). In contrast, reduction of ctc-[Pt(NH3)2(EM-Suc)(OAc)Cl2] yielded only the EM-succinate
conjugate (RT=28.9 min), and even after 79 h no free EM was observed (Figure 5B). The t1/2 for
the reduction of ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2] is 2.2 h and for the reduction of ctc-
[Pt(NH3)2(EM-Suc)(OAc)Cl2] is 6 h (Figure S37).
Free EM can be generated from ctc-[Pt(NH3)2(EM-Suc)(OAc)Cl2] only by hydrolysis of the
ester link to the succinate. Since the reduction of ctc-[Pt(NH3)2(EM-Suc)(OAc)Cl2] was nearly
complete after 30 h and no EM was observed after 79 h, the rate determining step for the release
of EM is the ester hydrolysis. To confirm this, we prepared the EM-succinate conjugate and
monitored the hydrolysis of the ester bond (t1/2 15 d -Figure S41).
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10.1002/anie.201910014
Angewandte Chemie International Edition
Figure 5 – The reduction of ctc-[Pt(NH3)2(EM-Carb)(OAc)Cl2] compared to the reduction
and hydrolysis of the ester linked ctc-[Pt(NH3)2(EM-Suc)(OAc)Cl2].
We combined Gem and taxol with cisplatin because they are potent anticancer drugs, used in
the clinic with platinum drugs.29 Preliminary cytotoxicity data against ovarian cancer cells (A2780)
and the cisplatin resistant line (A2780cisR) appear in Table 1.
Table 1- in vitro cytotoxicity data for a 72 h incubation of the compounds with the ovarian
cancer cell lines (A2780 and A2780cisR -left) and the in vivo efficacy study of cisPt(Gem)(PhB)
on the Lewis lung cancer murine model.
In vivo efficacy LLC
In vitro IC50 (M)
Daily
dose
(mg
tumor
weight (g)
Inhibition of
tumor
growth (%)
compound
Cancer cell lines
kg−1)
A2780
A2780cisR
0.0059±0.00004
0.003±0.00006
ctc-[Pt(NH3)2(Tax-
Carb)(OH)Cl2]
Taxol
0.004±0.002
0.0022±0.001
NDa
NDa
NDa
ND
NDa
NDa
ctc-[Pt(NH3)2(Gem-
Suc)(PhB)Cl2]
0.063 ±0.01
0.066 ±0.002
NDa
NDa
NDa
ctc-[Pt(NH3)2(Gem-
Carb)(PhB)Cl2]
cisplatin
gemcitabine
cisplatin+gemcitabine
(1:1)
0.005±0.0005
0.014±0.001
20
0.032±0.003
92
0.924±0.05
0.002±0.001
16.25±3.14
0.005±0.001
3
60
0.040±0.01
0.08±0.2
90
80
0.0031±0.0002
0.0121±0.0001
60+3
none
0.058±0.03
0.41±0.1
86
control
aND = Not determined
Taxol is much more potent than cisplatin and ctc-[Pt(NH3)2(Tax-Carb)(OH)Cl2] is only
slightly less potent than taxol. Gemcitabine is significantly more cytotoxic than cisplatin and also
somewhat more potent than ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] and ctc-[Pt(NH3)2(Gem-
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10.1002/anie.201910014
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Suc)(PhB)Cl2]. The triple-action ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] and ctc-[Pt(NH3)2(Gem-
Suc)(PhB)Cl2] have IC50 values in the low nM range, significantly more potent than cisplatin.
Interestingly, the nature of the linkage between the Gem and the PtIV has a large effect on
cytotoxicity. ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2], with the carbonate linkages is about 12- and 5-
fold more potent than its analog with the succinate bridge in A2780 and A2780cisR respectively.
The reasons for these differences are currently under investigation.
In vitro cytotoxicity does not predict the ability of the compound to reach the tumor and to
kill cancer cells. Moreover, it provides no information on the toxicity of the compounds. Therefore,
we carried out preliminary in vivo studies comparing cisplatin, gemcitabine, ctc-[Pt(NH3)2(Gem-
Carb)(PhB)Cl2] and co-treatment with cisplatin and gemcitabine in the murine Lewis Lung
Carcinoma (LLC) solid tumor model. Seven days after tumor inoculation the tumor-bearing mice
were randomized into vehicle control and treatment groups. Control mice received the vehicle
(0.5% DMSO (v/v) and 99.5% of a saline solution (v/v)), whereas treated groups received daily
doses of ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] (20 mg kg-1 in vehicle solution, orally) gemcitabine
(60 mg kg-1 in 0.9% saline solution, iv) or cisplatin (3 mg kg-1 in saline solution, iv). The tumor
growth was evaluated at day 15, and the results are summarized in Tables 1 and S1. Changes in
the body weights were monitored every two days (Figure S43).
Although most potent in vitro, gemcitabine was the least effective in vivo and induced a
reduction of tumor growth of about 80%. Oral administration of ctc-[Pt(NH3)2(Gem-
Carb)(PhB)Cl2] induced a ca. 92% reduction of the tumor mass compared to the control group,
very similar to the result obtained with cisplatin (~90% tumor inhibition). Remarkably, the time
course of body weight changes indicated that treatment with ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2]
induced a body weight loss lower than that induced by cisplatin (Figure S43). Gemcitabine induced
a reduction of tumor growth of about 80% and a significant anorexia, with a body weight loss
~20%. Co-treatment with cisplatin+gemcitabine was less effective than ctc-[Pt(NH3)2(Gem-
Carb)(PhB)Cl2] in inhibition of tumor growth (86 vs. 92%) but more importantly it was
significantly more toxic than ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] resulting in a body weight loss
>30%.
In summary, we developed a new approach for conjugating bioactive molecules with OH
groups to the axial position of PtIV such that following reduction of the PtIV, the bioactive molecule
is released in its active form. We accomplished this by using a carbonate as a bridge between the
hydroxido axial ligand of PtIV complexes and OH groups of the bioactive molecules. Following
reduction, the carbonated ligands lose CO2 and rapidly generate the original bioactive molecules
with an OH group. This allowed us to prepare multi-action PtIV derivatives of cisplatin with drugs
such as gemcitabine, taxol and estramustine.
Ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] was significantly more potent than cisplatin in vitro but
slightly less potent than gemcitabine and comparable to co-treatment with cisplatin+gemcitabine.
Importantly, in the in vivo studies ctc-[Pt(NH3)2(Gem-Carb)(PhB)Cl2] was more effective and less
toxic than the co-treatment with cisplatin and gemcitabine demonstrating in this case the advantage
of using multi-action prodrugs as compared to combination therapy.
We believe that this novel approach, paves the way for the design and synthesis of novel
classes of multi-action PtIV anticancer agents with a variety of bioactive moieties that have
hydroxyl functional groups that were hitherto unavailable to the medicinal chemists.
While succinates can be used to bridge the bioactive ligands with the PtIV, we have shown
that that the differences in the rates of reduction between PtIV complexes with carbonate and
succinate bridges to the hydroxy groups of the ligands, are not very large, but there is a huge
8
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10.1002/anie.201910014
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difference in the rates of release of the active moiety, due to the slow hydrolysis of the ester bond.
Nevertheless, these results may not necessarily reflect the relative rates of release of the bioactive
moieties in cells.
Acknowledgements
DG acknowledge the support of the Israel Science Foundation (grant 1002/18) and the Alex
Grass Center for Drug Design and synthesis. SK sincerely thanks Planning and Budgeting
Committee (PBC) of the Council for Higher Education (Israel) and The Hebrew University of
Jerusalem for postdoctoral fellowship.
Conflict of interest
The authors have no conflict of interest
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Table of contents
We prepared very potent multi-action PtIV prodrugs that following reduction release
cisplatin and OH containing drugs such as gemcitabine or taxol. Using carbonate to
bridge the axial PtIV OH and the OH of the drug facilitates rapid decarboxylation and
release of the active drug.
Keywords:
Anti-cancer
Gemcitabine
Platinum
Prodrug
Taxol
11
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