FLUFENAMIC ACID AND IT'S METAL COMPLEXES AS ANTICANCER

AGENTS
 
BY
BABA ANTHONIA OJONIMI
20CH1022
 
 
A SEMINAR REPORT SUBMITTED TO THE DEPARTMENT OF PURE AND
INDUSTRIAL CHEMISTRY, FACULTY OF NATURAL SCIENCES, PRINCE
ABUBAKAR AUDU UNIVERSITY, ANYIGBA.

IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR CHM 481

(SEMINAR)
 
SUPERVISOR: MR. ALIYU, A. A.
 
 
 
JUNE, 2023
 OUTLINE
INTRODUCTION

OVERVIEW OF CANCER DISEASE

CANCER DIAGNOSIS

CANCER TREATMENT

FLUFENAMIC ACID

PHYSICOCHEMICAL PROPERTIES OF FLUFENAMIC ACID

METALLIC COMPLEXES WITH FLUFENAMIC ACID AS ANTICANCER AGENTS.

CONCLUSION

REFERENCES
 INTRODUCTION
Despite advancements in modern medicine, cancer is a major cause of death worldwide, with a
death toll of 7.6 million or about 13% of all deaths per year [Liggett et al., 2014].

 This along with increasing life expectancies in the developed world produces more chances of
acquiring cancer and makes research into the mechanisms of cancer prevention a high priority.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that have been utilized for
their analgesic and antipyretic effects for centuries.

In more recent history, NSAIDs have also been widely used and studied for their anti-
inflammatory and chemopreventive properties.

There is still much work to be done elucidating the pathways of COX-independent activity of
Non-steroidal anti-inflammatory Drugs (NSAIDs), and this review primarily focuses on
intracellular molecular targets that are affected by flufenamic acid and its metallic complexes
 OVERVIEW OF CANCER DISEASE

Cancer, in general, is defined as a large group of diseases affecting any organ of

the body. It constitutes the foremost causes of morbidity and mortality across the

world, with an estimated 14.1 million new cases and approximately 8.2 million

deaths in the year 2012. Notably, over the coming two decades, the number of

cancer incidences is expected to rise by about 70% (WHO, 2017).

 FLUFENAMIC ACID

Flufenamic acid (HFluf) 2–[3–(trifluoromethyl) phenyl] aminobenzoic acid is a

member of anthranilic acid derivatives family (fenamates) [Tarushi et al., 2016]. It
belongs to a group of non-steroidal anti-inflammatory drugs (NSAIDs). Their
activity is based on the inhibition of cyclooxygenases COX–1 and COX–2 which
hamper conversion of the arachidonic acid to prostaglandins and are responsible
for anti-inflammatory action. Side effects are related to the well-known ability of
COX–1 to prompt gastric irritations [Sánchez–Borges et al., 2010].
Fig 1. Structure of Flufenamic Acid
 METALLIC COMPLEXES WITH FLUFENAMIC ACID AS
ANTICANCER AGENTS.

Having in mind the importance of Non-steroidal anti-inflamatory Drugs (NSAIDs) in

medicine and the enhanced activity of their metal complexes, a study by Dimiza et al. (2011)
and Terushi et al. (2012) initiated the synthesis and characterization of Cu(II), Ni, and Zn with
Non-steroidal anti-inflamatory Drugs (NSAIDs) as ligands [Dimiza et al., 2011; Terushi et al.,
2012].
The antioxidant activity of Non-steroidal anti-inflamatory Drugs (NSAIDs) and their
complexes may be related to their potential anticancer and antiinflammatory activity since
free radicals play an important role in the inflammatory process. The Non-steroidal anti-
inflamatory Drugs (NSAIDs) with a broad spectrum of activity can also act either as inhibitors
of free radical production or as radical scavengers [Gou et al., 2015].
Therefore, compounds possessing antioxidant properties could potentially have a crucial role
against inflammation and, thus, lead to potentially effective drugs. In this context, the
anticancer and anti-inflammatory effect of the above mentioned metal complexes with
flufenamic acid will be reviewed based on their antioxidant activities.
 COPPER (II) METAL COMPLEXES OF FLUFENAMIC ACID
The synthesis of Cu(II) complexes with the NSAID flufenamic acid in the presence of the O-donor
ligand N,N-dimethylformamide (DMF) resulting in the formation of complexes;
1. [Cu2(fluf)4(DMF)2],
2. [Cu(fluf)(bipyam)Cl],
3. [Cu(fluf)(phen)Cl],
4. [Cu(fluf)(bipy)Cl], and
5. [Cu(fluf)2(py)2], respectively.
 The complexes were characterized with physicochemical and spectroscopic techniques and their
electrochemical behavior was also investigated. The potential antioxidant ability of Hfluf and Cu
(II) complexes 1–5 has been evaluated in regard to DPPH, ABTS and hydroxyl radical scavenging
ability and has been compared to that of well-known antioxidant agents e.g. NDGA, BHT and
trolox. Therefore, these antioxidants effect may offer protection in rheumatoid arthritis and
inflammation and lead to potentially effective anticancer drugs.
 NICKEL COMPLEXES OF FLUFENAMIC ACID
As a continuation of our research in regard to metal-NSAID complexes, a study was
carried out by [Totta et al., 2013], which showed the interaction of Ni(II) with Hfluf in
the absence or presence of the nitrogen-donor ligands 2,2'-bipyridylamine (bipyam).
The resultant complexes were;
1. [Ni(fluf-O)2(MeOH)4],
2. [Ni(fluf -O,O')2(bipyam)],
3. [Ni(flufO)2(phen)(MeOH)2], and
4. [Ni(fluf-O)2(bipy)(MeOH)2],
These complexes were characterized by physicochemical (elemental analysis,
molecular conductivity and room-temperature magnetic measurements) and
spectroscopic (IR and UV-vis) techniques. The Ni-flufenamato complexes 1-4 are
equal DNA-binders and tighter albumin-binders than the corresponding Cu (II)-
flufenamato, Co (II) - flufenamato, Ni (II) - diclofenac and Ni (II)-mefenamato
complexes which makes these complexes better anticancer agents.
 ZINC COMPLEXES OF FLUFENAMIC ACID
 a study carried out by Terushi et al. (2016) showed the synthesis of five novel Zn(II) complexes
with flufenamic acid in the absence or presence of the nitrogen-donor ligands 2.2′- bipyridylamine
(bipyam), 2.2′-bipyridine (bipy), 1.10-phenanthroline (phen) or 2.2′-dipyridylketone oxime
(Hpko). The reaction of Zn(II) with deprotonated flufenamic acid resulted in the formation of
complex [Zn(fluf-O)2(H2O)4], 1, while in the presence of bipyam, bipy, phen or Hpko the
mononuclear complexes;
1. [Zn(fluf-O,O′)2(bipyam)],
2. [Zn(fluf-O,O′)2(bipy)],
3. [Zn(fluf-O)(phen)2(H2O)](fluf)·0.2MeOH,
4. 0.2MeOH, and
5. [Zn(fluf-O)2(Hpko-N,N′)2], respectively, were isolated.
 The antioxidant activity of the complexes was evaluated in regard to their ability to scavenge
DPPH, hydroxyl and ABTS radicals and to inhibit in vitro the activity of soybean LOX. The
present results concerning the in vitro SA- and DNA-binding of the complexes and their
antioxidant activity are promising in regard to the future biological significance of the complexes
 CONCLUSION
NSAIDs interact with many pathways in cancer cells. There are many promising
cyclooxygenase-independent mechanisms utilized by NSAIDs that provide
potential avenues for developing new and better drugs that minimize or eliminate
the undesirable side effects of cyclooxygenase inhibition such as gastric bleeding
and cardiovascular risks.
NSAIDs up-regulate a number of transcription factors such as the tumor
suppressors EGR-1, ATF3, and CHOP and down-regulate oncogenic transcription
factors Sp1 and β-catenin. Some NSAIDs also affect cytoskeletal reorganization
and loss of actin stress fibers.
The secreted tumor suppressor protein NAG-1 is induced by NSAIDs both in vitro
and in vivo, and other pathways. Thus, NSAIDs and improved derivatives of
NSAIDs have great potential as both chemotherapeutic and chemopreventive
agents in cancer.
 REFERENCE
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