Review

Potential of Organometallic Complex Compounds as Anticancer Drugs: A Review

Zaliari Nafisa Ardhani¹, Marvin Horale Pasaribu^2*, Risky Prisnanda¹, Maya Erliza Anggraeni¹,

Rendy Muhamad Iqbal^3,4

¹Department of Chemistry Education, Faculty of Education and Teacher Training, Universitas Palangka Raya,

Palangka Raya 74874, Central Kalimantan, Indonesia

²Department of Chemistry, Faculty of Mathematics and Science, Universitas Palangka Raya, Palangka

Raya 74874, Central Kalimantan, Indonesia

³Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, Skudai 81310, Johor,

Malaysia

⁴Advanced Membrane Technology Research Center (AMTEC), Faculty of Chemical and Energy

Engineering, Universiti Teknologi Malaysia, Skudai 81310, Johor, Malaysia

Abstract

Cancer is one of the deadliest diseases in the world. Currently, there are various types of anticancer

drugs that are used to treat cancer, but they still have various side effects that can interfere with the

quality of life of patients. Organometallic complexes (OCOs) are chemical compounds consisting of metal

atoms bonded to carbon atoms. OCOs have various potential to be used as anticancer drugs, including

their ability to specifically target cancer cells, inhibit cancer cell growth, and reduce the side effects of

other anticancer drugs. The mechanism of action of OCOs involves interactions with nucleophilic

molecules within the cell, including DNA, RNA, and proteins, as well as the formation of additional

platinum products. In this review, we will discuss organometallic compounds that can function as

anticancer drugs, such as platinum, ruthenium, iron, carboplatin, and oxaliplatin, which have been shown

to be effective in fighting cancer. We will also discuss the mechanism of action of these compounds in

cancer cells and the types of cancer cells that can be treated with organometallic compounds.

Keywords: Anticancer drugs, Organometallic compounds, , Reaction mechanism

*

Corresponding author

Email addresses: marvin.pasaribu@mipa.upr.ac.id

DOI: https://doi.org/10.22437/chp.v8i1.31409

Received January 18^th2024; Accepted June 28^th2024; Available online June 30^th2024

(https://creativecommons.org/licenses/by/4.0 )

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Chempublish Journal, 8(1) 2024, 29-41

Graphical Abstract

Introduction

exploration of novel therapeutic avenues, with

metal-based compounds emerging as promising

Complex compounds, essential for various

biological functions, play a critical role in human

physiology. Hemoglobin, a well-characterized

metallocomplex, exemplifies this concept by

facilitating oxygen transport throughout the

body. Disruptions in physiological homeostasis,

as observed in pathological conditions like

cancer, can be attributed to malfunctions in

candidates.

Traditionally,

organometallic

complexes were dismissed due to concerns

about their stability within the body. However,

recent advancements have yielded stable

organometallic complexes with potent anti-

cancer properties, even under physiological

conditions

possibilities for their application not only as

targeted anti-tumor agents, but also as

radiopharmaceuticals for both cancer diagnosis

and therapy.

[21]

.

This has opened exciting

these complex molecules ^[1]

.

Malignant neoplasms, commonly referred to as

cancers, pose a significant threat to human

health. These arise from uncontrolled cellular

proliferation – the abnormal and rapid division of

cells – that disrupts the delicate balance of tissue

homeostasis ^[2]. Mutations within the DNA

sequence, often triggered by environmental

factors like radiation, chemicals, or viruses ^[1]. are

a primary driver of this aberrant growth.

Furthermore, unlike benign tumors, cancers

exhibit the unique ability to invade surrounding

tissues and metastasize, establishing secondary

The past few years have witnessed a surge in the

development of transition metal complexes for

cancer therapy. Cisplatin, a platinum-based

complex, remains a cornerstone treatment for

solid tumors ^[11]. However, the search for even

more

effective

and

well-tolerated

agents

continues.

complexes

Ruthenium, iron, and osmium

are

emerging

as

promising

alternatives ^[27], with carboplatin and oxaliplatin

already demonstrating clinical efficacy ^[3,7]. A key

objective in this field is to minimize treatment-

tumors at distant sites within the body ^[11,12]

.

associated

side

effects.

Organometallic

The fight against cancer currently relies on a well-

established arsenal of therapies – surgery,

chemotherapy, and radiotherapy ^[28]. While these

approaches offer definitive solutions, their

limitations are increasingly recognized. Surgical

removal can be ineffective against disseminated

compounds, with their superior activity and

selectivity compared to inorganic counterparts,

offer a compelling path forward in this pursuit ^[22]

.

The

development

of

next-generation

organometallic anticancer agents hinges on the

design of novel ligands with enhanced selectivity

for specific targets on cancer cells. These ligands

can be further optimized to improve the in vivo

stability of the drug complex ^[21]. Targeted

cancers,

and

both

chemotherapy

and

radiotherapy, though potent, often inflict

significant side effects ^[10]. This has spurred the

30

Chempublish Journal, 8(1) 2024, 29-41

delivery via interaction with overexpressed

receptors on cancer cells has the potential to

minimize off-target effects associated with

toxicity, followed in 1989, finding application in

ovarian and other cancers. The 1980s also

witnessed the development of Ru(II) arene

complexes, exemplified by RAPTA-C, which

capitalized on arene ligands to enhance solubility

and stability within biological settings. The 1990s

saw the rise of ferrocene-based candidates like

current organometallic therapies^[4,5]

.

Materials and Methods

This journal review goes through several stages,

starting with (1) collecting various references in

Indonesian and English journal related to

ferrocifens,

demonstrating

activity

against

diverse cancers including breast cancer. Inspired

by the success of ruthenium (II) arenes, osmium

(II) arenes emerged as a research focus in the

1990s, targeting anti-proliferative effects against

drug-resistant cancer cells. Finally, oxaliplatin

received approval in 2002, further expanding the

repertoire of clinically relevant organometallic

anticancer drugs. Among the aforementioned

organometallic

components of anti-cancer drugs, (2) sorting out

important literature related to the

complex

compounds

as

predetermined topic, (3) examining the content

of the selected literature to gain an overview of

the

utilization

recent

developments

of organometallic

regarding

the

complex

organometallic

complexes,

only

cisplatin,

compounds as components of anti-cancer drugs,

considering their strengths and weaknesses. The

literature review in this article is based on 42

carboplatin, and oxaliplatin have garnered Food

and Drug Administration (FDA) approval for their

anticancer properties. Oxaliplatin, specifically,

finds application in combination with fluorouracil

and leucovorin for the treatment of colorectal

cancer. While Ru(II) arenes, ferrocenes, and

osmium(II) arenes demonstrated promising

preclinical and early clinical trial results, they

have yet to receive FDA endorsement for clinical

use. Ongoing research continues to meticulously

evaluate their efficacy and safety profiles, with

the ultimate goal of bringing some of these

compounds into the realm of approved

anticancer agents.

scientific

articles,

comprising

1

national

proceeding article, 1 accredited national journal

article, and 40 articles from leading international

journals such as Nature, Science Direct, ACS,

MDPI, SciELO, RSC, AACR, PNAS, Europe PMC,

ASCO,

Karger,

Chemistry

Europe,

and Spingerlink.

Result and Discussion

Organometallic complexes, characterized by

covalent metal-carbon bonds, hold immense

promise in the medical field, particularly as

This selection of six organometallic complexes

exemplifies the most prevalent class employed in

cancer therapy. These well-studied compounds,

anticancer

agents.

Cisplatin

(Cis-diamine-

dicholoroplatinum(II)), a clinically established

drug since 1980, exemplifies this potential. Its

mechanism involves DNA binding within cancer

cells, ultimately leading to cell death. Current

research is actively exploring a new generation of

organometallic complexes to address limitations

associated with existing agents, such as severe

side effects and the emergence of cancer cell

resistance.

including

cisplatin,

carboplatin,

ruthenium

complexes, ferrocenes, osmium complexes, and

oxaliplatin, find widespread application in clinical

settings. Their interaction with biomolecules like

DNA, RNA, and proteins contributes significantly

to our understanding of complex organometallic

mechanisms, a cornerstone for developing more

targeted and efficient anticancer agents. Notably,

the FDA-approved cisplatin and carboplatin,

along with promising new candidates based on

ruthenium and osmium, highlight the ongoing

research efforts. Similarly, oxaliplatin and

ferrocenes demonstrate encouraging preclinical

The exploration of organometallics as anticancer

agents represents a significant advancement in

medical chemistry. The discovery timeline began

with cisplatin, a pioneering platinum-based drug

approved in 1978 for various cancers like

testicular, ovarian, bladder, and lung carcinomas.

Carboplatin, a derivative of cisplatin with reduced

results

after

thorough

investigation.

The

structural diversity exhibited by these six

compounds, encompassing varied geometries

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Chempublish Journal, 8(1) 2024, 29-41

and ligand-metal centers, provides a unique

platform for exploring how such differences

translate to biological activity. This targeted

selection reflects the current research focus,

offering

a

comprehensive

overview

of

established knowledge and propelling future

studies in this promising field.

Table 1. Organometallic complexe compounds as anticancer agents

Organometallic

compound

Cisplatin

Molecular

structure

Planar

Reaction mecanism

Anticancer agent

Ref

Induces oxidative stress in cancer cells

Testicles

Ovary

[2]

tetragonal

Vesica urinaria

Lungs

Carboplatin

Efficiently binds to DNA, consequently

impeding the processes of replication

and transcription, ultimately triggering

apoptosis in cancer cells

Planar

tetragonal

Testicles

Ovary

Vesica urinaria

Lungs

[3]

Ru (II) arenes

Ferrocenes

As

a

cytotoxic agent capable of

Octahedral

Metalosena

Ovary

[4]

[5]

establishing covalent linkages with DNA

molecules

The ferrocenium cation reacts with the

Breast

superoxide

anion

to

regenerate

ferrocene and produce dioxygen

The substance has cytotoxic properties

through its ability to bind to DNA

The substance disrupts DNA replication

and transcription machinery by forming

DNA adducts.

Osmium

arenes

Oxaliplatin

(II)

Pseudo-

Octahedral

Oktahedral

Ovary

[6]

[7]

Pancreas

blood cell counts, and potential harm to the

Cisplatin. Cisplatin, initially known as Peyrone's

chloride following its synthesis in the late 19th

century, emerged as a revolutionary cancer

kidneys, nerves, hearing, heart, and liver ^[8]

.

Following cellular entry, cisplatin undergoes

activation within the cytoplasm. A water molecule

replaces a chloride ligand on the platinum center,

generating a potent electrophile. This activated

species can react with various nucleophiles,

including sulfhydryl groups on proteins and

nitrogen donors on nucleic acids. Notably,

cisplatin preferentially binds to purine residues

in cancer cell DNA, leading to DNA damage and

ultimately hindering cell division and triggering

apoptosis.

treatment

beginning

after

in

undergoing

1971. This

clinical

platinum-based

trials

organometallic complex received FDA approval

for treating testicular and ovarian cancers. Its

mechanism of action involves inducing tumor cell

death, making it a valuable tool in adjuvant

cancer therapy. Cisplatin demonstrates efficacy

against a broad spectrum of solid tumors,

including ovarian, testicular, bladder, and lung

cancers. Notably, its use often leads to favorable

early responses, ranging from complete disease

remission to partial response or disease

stabilization ^[2]. The synthesis of cisplatin as an

anticancer drug involves a reaction between

platinum(II) chloride with ammonia and sodium

chloride, with an alternative method utilizing

platinum(II) acetate and ammonia. However,

despite its effectiveness, cisplatin is not without

limitations. Platinum-based therapies are known

to induce dose-dependent side effects. Common

adverse effects encompass damage to healthy

cells, manifesting as nausea, vomiting, decreased

While cells maintain a homeostatic balance of

reactive

oxygen

species

(ROS)

under

physiological conditions through scavenger

systems, excessive ROS production under

oxidative stress can damage cellular proteins,

lipids, and DNA, contributing to cell death.

Importantly,

cisplatin-induced

cytotoxicity

heavily relies on the generation of oxidative

stress within the mitochondria of cancer cells.

This oxidative stress can modulate various

signaling pathways, including calcium signaling,

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Chempublish Journal, 8(1) 2024, 29-41

protein kinase

C

activity, Mitogen-Activated

components

chemotherapy triggering the immune system's

activation. The mechanism involves

combination of cellular stress and death signals

that culminate in a tumor-specific immune

response.

within

platinum-based

Protein Kinase (MAPK) pathways (JNK, p38 MAPK),

and the AKT pathway, further amplifying DNA

damage in cancer cells^[9]as shown in Figure 1.

Beyond its direct cytotoxic effects, cisplatin

exhibits the ability to induce immunogenic cell

death (ICD) at the cellular level. This translates to

a

Figure 1. Mechanisms of action of cisplatin on immunogenic molecular pathways

Cisplatin, for instance, cleaves calreticulin, a

protein within the endoplasmic reticulum. This

cleavage exposes a molecular signal recognized

by dendritic cells, prompting them to engulf and

process the dead cancer cells. Additionally, ATP

release and protein-1 mobility contribute to

dendritic cell activation and maturation by

Normally, IL-4 binding to its receptor leads to

STAT6 phosphorylation and its translocation to

the nucleus, where it promotes the transcription

of PD-L2. Disruption of this pathway by platinum

therapy leads to decreased PD-L2 expression,

ultimately enabling T cell activation against

cancer ^[10]

.

stimulating

purinoreceptor

recognition

oxaliplatin,

upregulates the expression of MHC class I

molecules on cancer cells. While this can enhance

immune evasion to some extent, it also promotes

dendritic cell maturation and subsequent T cell

proliferation. Platinum therapy further enhances

specific

P2RX7

receptor

receptors

–

the

and

TLR4.

the

pattern

Furthermore,

another

platinum-based

drug,

T

cell

expression of PD-L2, an inhibitory molecule on T

cells. This downregulation results from

activation

by

downregulating

the

decreased phosphorylation of STAT6, a protein

activated by the IL-4/STAT6 signaling pathway.

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Chempublish Journal, 8(1) 2024, 29-41

platinum (II), is

a

derivative of the well-

inflict greater DNA damage, impede DNA repair

pathways, or activate and potentiate apoptosis

hold promise for overcoming resistance and

established cancer drug cisplatin. While sharing a

similar mechanism of action focused on DNA

damage, carboplatin exhibits a distinct chemical

structure and toxicity profile compared to its

parent compound [II]. Synthesis of carboplatin

follows a similar approach to cisplatin. However,

a key difference lies in the substitution of

ammonia with 1,2-diaminopropane. Multiple

synthetic routes exist, utilizing either platinum (II)

chloride or acetate as starting materials

alongside 1,2-diaminopropane and sodium

diminishing tumor cell viability ^[16,17]

.

Carboplatin's therapeutic activity hinges on its

ability to traverse the cell membrane for

activation. Within the cellular environment, the

molecule undergoes hydrolysis of the 1,1-

cyclobutanedicarboxylate moiety, acquiring a

positive charge. This electrostatic transformation

facilitates

interaction

with

nucleophilic

chloride [II]. As

chemotherapeutic

a

leading platinum-based

biomolecules, including DNA, RNA, and proteins,

as illustrated in figure 3. Notably, carboplatin

agent, carboplatin finds

application in treating various cancers, including

testicular, ovarian, head and neck, and small cell

lung cancers ^[11]. Its primary target is cellular

DNA. By efficiently binding to DNA, carboplatin

disrupts replication and transcription, ultimately

leading to cancer cell death ^[12]. This DNA damage

can further impact numerous cellular signaling

binding can trigger the formation of additional

[18]

platinum adducts

.

The mechanism of

membrane

attachment of carboplatin to the N7 position of

purine bases, ultimately leading to the

permeation

involves

covalent

establishment of DNA-protein or DNA-DNA

crosslinks ^[19]

.

pathways,

triggering

either

apoptosis

(programmed cell death) or necrosis (cell death)

in tumor cells. Notably, carboplatin interactions

with DNA can result in the formation of various

DNA adducts, both within a single strand (intra-

While

exhibiting

lower

cytotoxic

potency

compared to cisplatin, carboplatin demonstrates

a more favorable side effect profile. This disparity

might be attributed to variations in the rate of

DNA adduct formation. The reduced reactivity of

carboplatin with nucleophilic biomolecules,

possibly due to the 1,1-cyclobutanedicarboxylate

group acting as a less efficient leaving group

compared to the chloride ligand in cisplatin,

could explain the difference in observed

chain)

and

between

different

strands

(interchain), further contributing to its anti-tumor

effects ^[13]as shown in Figure 2.

toxicities ^[13]

.

Figure 2. Formation of adducts between DNA

and Carboplatin

In vitro investigations have revealed mechanisms

by which cells develop resistance to carboplatin.

These mechanisms include enhanced drug

detoxification mediated by thiol groups within

metallothionein and glutathione, improved DNA

repair proficiency, and heightened tolerance to

DNA damage, ultimately leading to reduced

apoptosis and lower intracellular carboplatin

accumulation ^[14,15]. Consequently, strategies that

Figure 3. Hydrolysis of carboplatin in the cell.

Ctr1 is a high-affinity copper transporter

Carboplatin's interaction with DNA can induce a

spectrum of lesions, with interstrand cross-

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Chempublish Journal, 8(1) 2024, 29-41

linking (ISC) exhibiting the most pronounced

cytotoxic effect. These ISCs effectively halt DNA

replication and introduce errors during the

process. This ultimately leads to an accumulation

of cells in the G2/M phase of the cell cycle and

triggers apoptosis, or programmed cell death.

bidentate ligands to form the "legs." Notably, the

chelating nature of the bidentate ligand appears

to contribute to their anticancer activity. Ru(II)

arene complexes exhibit both hydrophilic and

hydrophobic properties, potentially leading to

not only additive but also synergistic effects in

their interaction with biological targets [4].

Furthermore, the robust Ru(II) arene unit

facilitates the incorporation of diverse ancillary

ligands, enabling the creation of structurally

varied complexes with distinct modes of

biomolecular interaction. This versatility holds

significant promise for the development of novel

and potent anticancer drugs. Synthetically, Ru(II)

arenes can be obtained from ruthenium(II)

carbonyl precursors through ligand substitution

reactions. Alternatively, ruthenium(II) halide

compounds can serve as starting materials,

Conversely,

single-strand

DNA

alkylation,

another consequence of carboplatin interaction,

is readily repaired by the cell's DNA repair

machinery. However, interstrand cross-links, a

hallmark of bifunctional alkylating agents like

carboplatin, necessitate more intricate repair

mechanisms due to their complex structure ^[20]

.

Cellular recognition of platinum-induced DNA

damage relies on the intricate machinery of DNA

repair pathways. Within the chromatin structure,

the repair system might necessitate the

unwinding of the damaged double-stranded DNA

from the nucleosome, the fundamental unit of

chromatin. Elucidating the interaction between

platinum bound to nucleosomal DNA is therefore

crucial for understanding the cellular recognition

process ^[20]. The DNA mismatch repair (MMR)

system plays a pivotal role in replication fidelity

by preventing errors arising from mutations.

MMR recognition relies on the distortion of DNA

caused by the presence of 6-thioguanine and

other carboplatin-derived adducts, generating a

damage signal potentially leading to apoptosis

initiation. This mechanism suggests a role for

MMR proteins in detecting carboplatin-induced

DNA lesions. Consequently, loss of functional

MMR can contribute to carboplatin resistance,

potentially stemming from the inability to

recognize the complex formed by DNA adducts

with platinum-based drugs^[20]. Similar to cisplatin,

carboplatin can induce nausea and vomiting,

albeit with a less severe incidence. Additionally,

carboplatin shares the nephrotoxic potential of

cisplatin, leading to kidney damage and

potentially progressing to chronic kidney disease.

utilizing

either

ligand

substitution

or

transmetalation strategies.

Figure 4. RAPTA-C (a) and RM175 (b) are typical

examples of 18-electron Ru arenes complexes

with a "piano-bench" geometry, in which the n-

arene ring stabilizes the 2+ oxidation state of the

central Ru metal.

The Sadler group pioneered the exploration of

ruthenium(II)

complexes

for

anticancer

applications, with RM175 [Ru(biphenyl)Cl(en)]+

(en = 1,2-ethylenediamine) as one of the first

candidates (Figure 4). This complex exhibits a

pseudo-octahedral geometry, resembling

a

"piano stool" with a monodentate chloride

ligand, a bidentate ethylenediamine ligand, and a

biphenyl arene ligand occupying the three

coordination sites. While initially designed to

target

DNA,

RM175's

development

also

capitalized on the advantages of the +2 oxidation

state, which bypasses the need for cellular

reduction for activation.

The hydrophobic surface conferred by the arene

substituents is believed to facilitate cellular

diffusion across the lipophilic plasma membrane

^[21]. Upon entering the cell, the complex likely

undergoes activation through ligand exchange at

Ru (II) arenes. Recent research on ruthenium-

based anticancer agents has identified Ru(II) half-

sandwich arene complexes containing the 1,3,5-

triaza-7-phosphatricyclo-[3.3.1.1]decane

(PTA)

ligand (RAPTA) as particularly promising

candidates. These complexes adopt a "piano

stool" geometry, where n-arene ligands occupy

the "seat" and combine with mono- and

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Chempublish Journal, 8(1) 2024, 29-41

the monodentate site prior to DNA binding^[22,23]

This activation mechanism resembles cisplatin,

where the halogen atom acts as a leaving group

.

readily displaced monodentate ligand results in a

diminished cytotoxic effect [31]. While ruthenium

complexes hold promise as therapeutic agents,

their administration can be associated with

adverse effects on red blood cells, potentially

leading to anemia and other blood disorders

[32]. Additionally, some ruthenium complexes

exhibit nephrotoxic properties similar to cisplatin

and carboplatin, potentially causing kidney

damage and progression to chronic kidney

disease

followed by aquation, creating

a

vacant

coordination site for subsequent covalent

bonding with the N7 atom of guanine within the

[21]

DNA double helix

.

While ruthenium(II)

complexes demonstrably bind to guanine

residues in DNA ^[24], the expanded arene moiety

in RM175 is postulated to enable hydrophobic

interactions via intercalation between DNA base

pairs^[25]. The relatively free rotation of the

biphenyl ligand around the Ru(II) center imparts

flexibility to the complex, potentially minimizing

steric hindrance and enhancing its DNA binding

affinity. This flexibility allows RM175 to achieve

Ferrocenes. Despite its relatively low toxicity, the

organometallic ferrocene complex Fe(η⁵-C₅H₅)₂

(figure 5a) can be oxidized to the ferrocenium

cation [Fe(η⁵-C₅H₅)₂]⁺, which exhibits cytotoxicity

against various cancer cell lines. Synthetically,

ferrocene derivatives can be obtained from

both

intercalation

and

guanine

binding

simultaneously,

which

could explain

the

observed resistance of RM175-DNA adducts to

repair mechanisms compared to cisplatin-DNA

adducts. These observations contribute to

understanding the lack of cross-resistance

between RM175 and platinum-based drugs.

iron(II)

precursors

via

cyclopentadienide

reactions. The precise mechanism of the

ferrocenium cation's antiproliferative activity

remains elusive, although hydroxyl radical

generation likely plays a role in DNA and cell

membrane

damage

within

cancer

cells,

A key feature of this complex is the pre-existing

lower oxidation state of the metal center, which

may contribute to its cytotoxic activity [26]. The n-

donor/acceptor properties of the arene ligands

offer stability to the +2 oxidation state.

Additionally, the bidentate XY ligand enhances

the overall structural integrity and allows for fine-

tuning of the electronic properties at the metal

center. Notably, the monodentate ligand Z serves

a crucial role in molecular activation. If readily

displaced, such as in the case of a halide ligand,

it can vacate a coordination site for interaction

ultimately leading to cell death [31]. Conjugating

ferrocene with tamoxifen, a known antiestrogen,

yields

"ferrocifene"

derivatives

(e.g.,

that

HO(CH₂)₃C(Fe)=C(C₆H₄OH)₂, in figure

6

demonstrate enhanced antiproliferative activity

against cancer cell lines. Chemical oxidation of

these ferrocifene derivatives leads to the

formation of unique tetrahydrofuran-substituted

methidequinones

(QM)

through

internal

cyclization. Notably, the ferrocenyl group acts as

both a reversible intramolecular redox antenna

and a stabilizing carbocation modulator in this

with biomolecules ^[22,27]

.

complex^[32]

.

Ru(II) arene complexes exhibit promising

cytotoxic activity against human ovarian cancer

Another promising class of anticancer agents

combines ferrocenyl moieties with iminosugars

cell lines, demonstrating potency comparable to

(Figure

5b).

These

ferrocenyl-iminosugar

[28]

cisplatin and carboplatin in some cases

.

conjugates exhibit dual functionality, inhibiting

Research efforts have identified several key

structure-activity relationships^[29,30]. One such

relationship involves the chelating ligand and the

fucosidase activity and exerting antiproliferative

[33]

effects

.

Studies have shown significant

antiproliferative activity against MDA-MB-231

and SK-MEL28 cell lines for these conjugates.

Functionalized ferrocene can also serve as a

precursor for the synthesis of heterometallic

eguanidine Pt(II) complexes with antiproliferative

properties. These Fe-Pt complexes containing

guanidine ligands (Figures 5c and 6d) exhibit

leaving

group.

When

ethylenediamine

is

employed as the chelating ligand and chloride

serves as the leaving group, cytotoxicity against

A2780 human ovarian cancer cells increases with

the size of the coordinated arenes^[28]. Conversely,

substituting the chelating ligand with a more

36

Chempublish Journal, 8(1) 2024, 29-41

activity against various human cancer cell lines,

with GI₅₀ values ranging from 1.4 to 2.6 μM.

Notably, these complexes demonstrate superior

cytotoxicity compared to cisplatin against

resistant T-47D and WiDr cell lines ^[34]

.

(a)

(b)

(c)

(d)

Figure 5. Molecular structures of ferrocene complex (a), conjugated ferroceneeiminosugar complex (b)

and Pt(II) eguanidine complex functionalized with ferrocenee (c)

Ferrocene-based

compounds

has

been

panel of 809 cancer cell lines (Sanger panel).

Furthermore, in vivo testing suggests their

efficacy. The proposed mechanism of cell death

involves a redox process, triggering the rapid

generation of intracellular reactive oxygen

species (ROS), particularly superoxide. A recent

associated with hematological toxicities, such as

anemia and thrombocytopenia. Additionally,

gastrointestinal side effects, including nausea

and vomiting, may also occur.

Osmium (II). Os(II)-arene complexes containing

specific phenylazopyridine ligands and iodide

(Figure 7a) demonstrate enhanced potency and

reduced reactivity compared to complexes with

study

employing

focused

nano-X-ray

fluorescence revealed osmium localization within

specific cellular regions resembling mitochondria

following treatment with physiologically relevant

conjugate doses. These findings highlight the

promise of this complex as a candidate for

monodentate

ligands^[35]

.

These

complexes

exhibit not only superior cytotoxicity to cisplatin

in NCI-60 cell line studies but also a remarkable

49-fold higher average activity against a broader

preclinical development ^[36]

.

(a)

(b)

(c)

(d)

Figure 7. Molecular structures of Os(II)-arenes complex (a), iodide-Os(II)-azopyridine conjugate (b),

[Os₄(η⁶-p-cym)₄(μ²-OH)₄(pap)₂][PF₆]₄(1-[PF₆]₄) complex (c), and [Os₄(η⁶-p-cym)₄(μ²-OH)₄(prz)₂][PF₆]₄(2-

[PF₆]₄) complex (d).

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Chempublish Journal, 8(1) 2024, 29-41

manifesting as numbness, tingling, and muscle

weakness.

Oxaliplatin.

cyclohexanediamine)platinum(II) oxalate), a DNA

intercalating agent, presents as newer

Oxaliplatin

(cis-diammine-(1,2-

a

platinum-based chemotherapeutic with superior

antitumor activity compared to cisplatin and

carboplatin. This complex is often used in

combination regimens for treating various

cancers. Its synthesis involves the reaction of

platinum(II)

precursors

with

1,2-

Figure 8. The possible pathways connecting the

intracellular activation of azopyridinium iodide

Os(II) arena anticancer complex with Ca

mobilization, mitochondrial dysfunction, ROS

generation, and cell death.

cyclohexanediamine and oxalic acid. In vitro

studies utilizing the NCI-60 drug screening panel

demonstrate oxaliplatin's generally superior

efficacy compared to cisplatin, as measured by

IG50 values. The mechanism of action involves

disruption of DNA replication and transcription

through the formation of intrastrand DNA

adducts, particularly Pt-guanosine-guanosine (Pt-

GG) adducts. These Pt-DNA complexes at the

nucleotide level ultimately trigger activation of

Similar to cisplatin and carboplatin, osmium

complexes can induce nephrotoxicity, potentially

leading to kidney damage and progression to

chronic

kidney

disease.

Additionally,

administration of high-dose osmium complexes

has been associated with neurotoxic effects,

DNA

repair

mechanisms

or

apoptosis

pathways^[7].

Tabel 2. Advantage and Shortage of each organometallic complex compound as an anticancer agent

Types of

Organometallic

Advantage

Shortage

Ref

Cisplatin

As an initial therapeutic response

associated with complete disease

remission, partial response, or

disease stabilization.

Has side effects such as: nausea and

vomiting, decreased blood cells, damage

to the kidneys, nerves, decreased

hearing, heart, and liver.

[8]

Carboplatin

Pharmacodynamics of carboplatin,

has fewer side effects than its

precursor cisplatin.

Has side effects such as: Anemia, nausea,

vomiting, abdominal pain, diarrhea,

[13]

contipation,

mucous

membrane

disorders, and spinal cord suppression.

Lack of cross-resistance with platinum

Ru (II)arenes

Shows promising cytotoxic activity

against cancer cell lines.

Generates hydroxyl radicals in

cancer cells that can cause damage

to DNA and cell membranes

[28]

[31]

Ferrocenes

The mechanism by which [Fe(h5-

C5H5)2]+ exerts its antiproliferative

effect is not fully understood.

Osmium (II) arenes

Common toxicities that may reduce

the side effects of chemotherapy

Considered the standard first-line

treatment for colorectal cancer

Lower reactivity of transition metal

bonds

Most oxiplatin studies have not been

able to significantly improve survival

[37]

[40]

Oxaliplatin

Currently,

chemotherapeutics,

remains

treatment. Recent research suggests that

overexpression of DNA repair proteins, such as

DNA polymerase beta (Pol β), may play a role in

resistance

to

platinum-based

oxaliplatin,

this resistance. A study by Yang et al. (2010)

demonstrated that tumors with elevated Pol β

expression exhibited increased sensitivity to

oxaliplatin-induced DNA damage. This finding

highlights the potential importance of protein

including

a

significant challenge in cancer

expression

profiles

in

predicting

patient

38

Chempublish Journal, 8(1) 2024, 29-41

response to oxaliplatin therapy.

formation of Pt-DNA adducts, oxaliplatin's

mechanism of action likely involves additional

Beyond the

osmium, and oxaliplatin, have been the focus of

research for the development of effective and

efficient anti-cancer drugs. The mechanism of

action of organometallic complexes involves

interaction with nucleophilic molecules inside the

cell, including DNA, RNA, and proteins. This

interaction can cause damage to DNA, RNA, or

proteins, which can lead to cancer cell death.

cellular targets.

Therefore, a comprehensive

understanding of both oxaliplatin's interaction

with DNA repair pathways and its effect on

protein expression profiles is essential for

optimizing platinum-based cancer therapies ^[39]

.

Although

organometallic

complexes

show

Oxaliplatin demonstrates limited clinical efficacy

as a single agent and is typically used in

combination regimens. The FOLFOX regimen,

combining oxaliplatin with 5-fluorouracil (5-FU)

and leucovorin (LV), is the current standard first-

line treatment for colorectal cancer. Clinical trials

are also investigating the efficacy of FOLFOX for

other malignancies, such as pancreatic cancer.

The order of administration, duration, and

cytotoxicity within these combination regimens

are complex and require careful optimization for

individual patients due to variability in efficacy.

Unfortunately, existing studies on combination

potential as anti-cancer drugs, their use still has

some advantages and disadvantages. The

advantages of organometallic complexes are

their effectiveness in killing cancer cells. The

disadvantages

are

that

organometallic

complexes can cause side effects, such as

nausea, vomiting, and kidney damage. Therefore,

further research is needed to optimize the use of

organometallic complexes as anti-cancer drugs

with minimal side effects.

Acknowledgement

therapies

with

oxaliplatin

haven't

shown

This research supported by Department of

Chemistry Education, Faculty of Education and

Teacher Training; and Department of Chemistry,

Faculty of Mathematics and Natural Science,

Universitas Palangka Raya.

significant improvement in overall survival rates,

highlighting the need for novel systemic

therapies for complex cancers ^[40]

.

Adjuvant therapy using oxaliplatin following

surgical resection for colorectal cancer has

shown modest improvements in survival.

However, a comprehensive understanding of

Author Contribution

Conceptualization, Z.A.D, R.P; Methodology,

M.E.A; Software, R.M.I; Validation, M.H.P, Z.N.A;

oxaliplatin's

efficacy

compared

to

other

treatment options in this context remains

elusive^[41]. Emerging evidence suggests that

oxaliplatin may target protein networks beyond

Formal

Analysis,

R.M.I;

Investigation,

-.;

Resources, -.; Data Curation, -; Writing – Original

Draft Preparation, M.E.A; Writing – Review &

Editing, M.H.P; Visualization, R.P; Supervision,

M.H.P.

DNA,

potentially

forming

platinum-protein

adducts.

Further investigation into these

interactions is crucial, as they may play a role

beyond simple drug inactivation ^[42]. Oxaliplatin

can be associated with neurotoxic side effects,

such as numbness, tingling, and muscle

weakness, predominantly affecting the hands

and feet. Additionally, gastrointestinal toxicities,

including nausea and vomiting, may also occur.

Conflic of Interest

The authors declare no conflict of interest

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