ANTI-NEOPLASTIC

AGENTS
Presented by Group 11
INTRODUCTION
◦ Cancer is a term used for diseases in which abnormal cells divide without control and can
invade other tissues. Cancer cells can spread to other parts of the body through the blood and
lymph systems, this process is called metastasis.
◦ Characteristics of Cancer Cells:
◦ Cancer involves the development and reproduction of abnormal cells
◦ Cancer cells are usually nonfunctional
◦ Cancer cell growth is not subject to normal body control mechanisms
◦ Cancer cells eventually metastasize to other organs via the circulatory and lymphatic
systems. 
TYPES OF TUMOR
• Benign: noncancerous and not an
immediate threat to life, even though
treatment eventually may be required
for health.
• Malignant: tending to worsen and
cause death, invasive and metastasis
ANTINEOPLASTIC AGENTS
◦ The Antineoplastic agents or anticancer drugs represent a large and diverse class of
medications. They generally have limited but important uses, and often have significant
hepatotoxicity.
◦ The antineoplastic agents are not easily classified. They are categorized as
A. Alkylating agent,
B. Antimetabolites,
C. Natural products,
D. Hormones and antagonists, and
E. Miscellaneous.
In recent years, however, the miscellaneous group has come to include some of the most
important agents.
THE CELL CYCLE AND
CHEMOTHERAPEUTIC
DRUGS
ANTIMETABOLITES
Presented by Soubia Aamir
Introduction
◦ Antimetabolites are defined as interfering with the synthesis of the DNA constituents; they are
structural analogs, either of purine and pyrimidine bases (or the corresponding nucleosides), or
of folate cofactors, which are involved in several steps of purine and pyrimidine biosynthesis.
Their first mechanism of action is, therefore, to induce depletion in nucleotides inducing in
turn an inhibition of DNA replication. However, some of them are able to get inserted
fraudulently into nucleic acids, inducing structural abnormalities leading to cell death by other
mechanisms, including DNA breaks.
◦ Antifolates: Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate
◦ Purine Analogues: Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Thioguanine
◦ Pyrimidine Analogues: Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine,
Fluorouracil, Gemcitabine, Trifluridine/Tipracil
Antifolate: methotrexate

◦ Methotrexate is an antineoplastic and immunosuppressive agent widely used in the therapy

of leukemia, lymphoma, solid tumors, psoriasis, and rheumatoid arthritis
◦ IUPAC nomenclature
(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid
Mechanism of action
i. Methotrexate competitively inhibits dihydrofolate reductase.
ii. The synthesis of tetrahydrofolate decreases.
iii. Due to this, the synthesis of nucleoside thymidine also decreases.
iv. This inhibits the synthesis of DNA.
v. Further, the purine synthesis is also inhibited by the methotrexate as the tetrahydrofolate is important for
the synthesis of purine also
Structure-activity relationship
◦ Replacement of glutamate tail with lipophilic agents can increase the transportation of the drug through
the folate carrier system.
◦ Thiourea entity can increase the activity of the drug
◦ Replacement of Thiazole with imidazole will increase the activity of the drug.
◦ Tetrahydroquinazolines derivatives will affect the ligand-enzyme interaction in a positive manner, where
the dibenzodiazepine ring will show the pharmacophoric features which are essential for the activity of
the drug.
◦ Substitution at the 2nd, 3rd, and 6th positions in the quinazolinone nucleus will inhibit the action of the drug.
◦ Substitution at ortho and para positions in the phenyl ring will decrease the tendency of the drug to bind
with DHFR, thus decreasing the activity of the drug.
◦ Combining the drug with copper metal can also increase the activity of the drug.
Purine analogue: azathioprine
◦ Azathioprine is an imidazolyl derivative and prodrug of
mercaptopurine that inhibits lymphocyte function by
antagonism of purine metabolism, thus inhibiting DNA,
RNA, and subsequent protein synthesis. Azathioprine
inhibits the maturation of T cells and blocks delayed
hypersensitivity reactions; it also has anti-inflammatory
activity
◦ IUPAC nomenclature
6-[(1-Methyl-4-nitro-1H-imidazole-5-yl)sulfanyl]-7H-purine
Mechanism of action
i. Azathioprine inhibits the synthesis of purine in the cell.
ii. This will further lead to the inhibition of the synthesis of DNA and RNA.
iii. Azathioprine also interacts with cellular metabolism and results in the inhibition of mitosis.
Structure-activity relationship
◦ The activity of the drug increases with an increase in the carbon chain up to 15-16 carbons, after that, it
again decreases.
◦ Substituent at position 6 which can lead to an increase in the resonance at the 6th position will lead to an
increase in the activity of the drug.
◦ Introduction of the hydrophobic substituent at the 6th position will increase the activity of the drug.
◦ Substitutions at the 2nd position may not change the activity of the drug, or they may decrease the
activity of the drug depending upon the type of substituent.
pyramidine analog: fluorouracil (5-FU)
◦ Fluorouracil (5-FU) is a pyrimidine analog used as
an antineoplastic agent to treat multiple solid
tumors including colon, rectal, breast, gastric,
pancreatic, ovarian, bladder, and liver cancer.
◦ IUPAC nomenclature:
5-Fluoro-1H,3H-pyrimidine-2,4-dione
Mechanism of action
I. 5-Fluororacil binds with thymidylate synthase enzyme to form a ternary complex system.
II. Formation of thymidylate from uracil is inhibited due to the complex formation.
III. In the absence of thymidylate, DNA, and RNA synthesis are inhibited.
IV. The drug can also get inserted in the place of UTP in the RNA, which results in the inhibition of
protein synthesis in the cell.
V. This overall mechanism leads o the death of the cell.
Structural Activity Relationship
◦ The molar refractivity of the Y substituent will produce an
increase in the activity of the drug.
◦ Substituent at Y with (CH2)3NRiR2 with R2 = COCH3,
COC6H5, or COOCeH5 will produce a negative effect on
the activity of the drug.
◦ SH at the 4th position will increase the activity of the drug.
◦ Substituents that are bulky in nature at the Y position will
produce a negative effect on activity due to steric hindrance.
◦ Electron withdrawing groups at the 5th position will increase
the activity of the drug.
ALKYLATING
AGENTS
Presented by YUSRA SHEIKH
Altretamine
◦ Introduction:
◦ Altretamine is an antineoplastic agent used in palliative treatment of persistent or recurrent
ovarian cancer.

◦ STRUCTURE:
Mechanism of Action:
◦ Altretamine (al tret' a meen) is a synthetic, orally available alkylating
agent belonging to the methylmelamine class of these agents. The alkylating
agents act by causing modification and cross linking of DNA, thus inhibiting
DNA, RNA and protein synthesis and causing cell death in rapidly dividing
cells.
Synthesis:

◦ The synthesis method involves the conversion of cyanuric chloride (2) into altretamine (1) by
dimethylamination of 2 with an aqueous solution of 40% dimethylamine and potassium hydroxide in 1, -
dioxan 4in one step to give altretamine (1) in high yield.
Vincristine:
Introduction:
Vincristine is a chemotherapy drug that belongs to a group of drugs called vinca alkaloids. Vincristine works
by stopping the cancer cells from separating into 2 new cells. So, it stops the growth of the cancer.

◦ Structure:
Mechanism of action:
The mechanism of action of vincristine sulfate has been related to the inhibition of
microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at the
metaphase stage.
SAR of VINCRISTINE:
Aryl or heteroaryl compounds decreases the activity of the drug.
◦ Strongly polar or charged groups also decreases the activity of the drug.
◦ Decreasing in the polarity of the substituent produces more active analogues of the drug.
◦ Decreasing the charge on the substituent also increases the activity of the analogues of the drug.
◦ The activity of the drug can be restores by the introduction of the lipophillic linker such as
thioether.
◦ Small and uncharged molecules increase the activity and shows best results.
Synthesis of vincristine:
◦ The treatment of chloroindolenine with TFA.
◦ Methanolysis of TFA leads to the production of tertiary alcohol.
◦ Treatment with 2-mercaptoethanol and 1,8-diazabicycloundec-7-ene (DBU) in acetone leading
to the formation of secondary amine.
◦ Secondary amine undergoes into further transformation to yield vinblastine .
◦ Formylation (introdcution of CHO group) of the N1 position of vinblastine to produce
vincristine.
PROTEIN KINASE
INHIBITORS:
Prepared by Rabia Naeem khan
INTRODUCTION
◦ A protein kinase is a kinase enzyme that modifies other
proteins by chemically adding phosphate groups to them
(phosphorylation).
◦ Phosphorylation usually results in a functional change of
the target protein (substrate) by changing enzyme activity,
cellular location, or association with other proteins.
◦ The hhuman genome contains about 500 protein kinase
genes; they constitute about 2% of all eukaryotic genes.
Imatinib
Imatinib is a type of cancer growth blocker called a tyrosine kinase inhibitor (TKI).Tyrosine kinases
are proteins that cells use to signal to each other to grow. They act as chemical messengers. There are
a number of different tyrosine kinases and blocking them stops the cancer cells growing.
Mechanism of Action
1.It inhibits the Bcr-AbI tyrosine kinase.

2.This inhibits the proliferation and thus, induction of apoptosis in cells.

Structural Activity Relationship
◦ Imatinib is a 2-Phenylaminopyrimidine derivative neoplastic
agent.
◦ Amide group as a substituent at phenyl group shows inhibitory
action against tyrosine kinases.
◦ Substitution at 6 position of diaminophenyl ring abolished the
activity against PKC.
◦ Introduction of methyl group in an ortho position to the amino
group can increase the selectivity of Bcr-Abl.
Synthesis
◦ Imatinib can be synthesized by the reaction of 4-
methyl-N-3-(4-pyridine-3-yl-pyrimidine-2-yl)-1,2-
benzenediamine with 4-(4-methyl-piperazine-1-
methyl)-benzoic ester in the presence of base in a non-
protonic organic solvent.
Gefitinib
◦ Gefitinib is a tyrosine kinase inhibitor used as first-line
therapy to treat non-small cell lung carcinoma.
Mechanism of Action
◦ Inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with
transmembrane cell surface receptors, including the tyrosine kinases associated with the
epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many
normal cells and cancer cells.
Structure Activity Relationship
◦ Gefitinib is a 4-anilinoquinazoline structure.
◦ It occupies aniline ring, quinazoline part, morpholine ring, secondary
amine group and methoxy group.
◦ Aniline ring occupies the hydrophobic pocket that bind with ribose
pocket.
◦ Quinazoline structure binds to the same region of the purine ring of
ATP.
HORMONAL
AGENTS
Presented by SYEDA TASVEER FUZAIL AZEEMI
HORMONAL AGENTS
◦ Hormonal agents are widely used in curative and palliative treatment of hormone-dependent tumors.
Tamoxifen, toremifene,
◦ They are nonsteroidal antiestrogens with weak estrogenic agonist effects.
◦ Hormone therapy uses synthetic hormones to block the effect of the body's natural hormones. The aim
is to lower the amount of hormones the tumour receives.
◦ FLUTAMIDE:
is a first generation and oral nonsteroidal antiandrogen that has been used widely in prostate cancer
therapy.
Flutamide is frequently associated with minor serum aminotransferase elevations and has been linked to
numerous cases of acute liver injury, which are frequently severe and can be fatal.
ANTI ANDROGENS
◦ Mechanism of Injury
◦ The mechanism of injury due to flutamide is not clearly understood. Flutamide is extensively metabolized
by the liver, and a common hypothesis is that flutamide is metabolized by the cytochrome P450 system
(CYP 3A4) to a toxic intermediate.
◦ Side effects: 
◦ in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes.
Conversely, the medication has fewer side effects and is better-tolerated in women with the most common
side effect being dry skin. Diarrhea and elevated liver enzymes can occur in both sexes. Rarely, flutamide
can cause liver damage, lung disease, sensitivity to light, elevated methemoglobin, elevated
sulfhemoglobin, and deficient neutrophils Numerous cases of liver failure and death have been reported,
which has limited the use of flutamide.
ANTI ANDROGENS
ANTI ESTROGENS
Tamoxifen is a nonsteroidal antiestrogen that is widely used in the treatment and prevention of
breast cancer. Long term tamoxifen therapy has been associated with development of fatty liver,
steatohepatitis, cirrhosis, and rare instances of clinically apparent acute liver injury.

◦ Mechanism of Injury
◦ The acute form of liver injury attributed to tamoxifen use is probably due to an reaction to a
metabolite of the medication rather than its estrogenic effects. In contrast, the induction of fatty
liver are likely due to estrogenic effects on the liver in the setting of a genetic predisposition to
fatty liver disease.
ANTI ESTROGENS
◦ How does tamoxifen work?
◦ Many breast cancers are stimulated to grow by the female sex hormones oestrogen and
progesterone. These breast cancers are called hormone sensitive or hormone receptor positive
breast cancers.
◦ You can have tamoxifen if you are pre menopausal  or post menopausal . If you are pre
menopausal you might have it on its own or with another drug to stop the ovaries from
working. This is called ovarian suppression.  
◦ Men have a small amount of oestrogen and progesterone in their body. This means they can
develop hormone positive breast cancer.  
ANTI ESTROGENS
◦ COMMON SIDE EFFECTS
◦ These side effects happen in more than 10 in 100 people (more than 10%). You might have one or more of them. They
include:
◦ Hot flushes and sweats 
◦ We have some tips for coping with hot flushes in women and hot flushes in men. This information also includes some
of the possible treatments.
◦ Fluid build up 
◦ You may feel sick when you first start taking tamoxifen,
◦ Tiredness and weakness (fatigue)
◦ Tiredness and weakness (fatigue) can happen during and after treatment. Doing gentle exercises each day can keep
your energy up.
◦ Vaginal changes
◦ This might include bleeding or discharge from the vagina. Talk to your doctor or nurse if you have any bleeding or
discharge.
◦ Skin rash
HORMONAL AGENTS
ANTI ESTROGENS
PEPTIDE HORMONES
◦ Introduction
◦ Lanreotide is a synthetic polypeptide analogue of somatostatin that resembles the native hormone in
its ability to suppress levels and activity of growth hormone, insulin, glucagon and many other
gastrointestinal peptides. Because its half-life is longer than somatostatin, lanreotide can be used
clinically to treat neuroendocrine tumors that secrete excessive amounts of growth hormone
(acromegaly) or other active hormones or neuropeptides.
◦ Mechanism of Injury
◦ Lanreotide, like somatostatin, decreases cholecystokinin secretion, gall bladder contractility and bile
secretion, perhaps accounting for the high rate of gall bladder sludge and stone formation with long
term use.. Lanreotide is a polypeptide and, as such, should not have direct or even indirect hepatic
toxicity. On the other hand, lanreotide has multiple effects on the gastrointestinal tract, including
effects on gastrointestinal hormone levels, motility, transit time, bacterial flora, and bile acid
concentrations etc
PEPTIDE HORMONES
◦ Lanreotide (Somatuline)
◦ Lanreotide (also known as Somatuline) is a man made (synthetic) version of the natural hormone somatostatin.
◦ You might have it as a treatment:
◦ for carcinoid syndrome
◦ to control the growth of some advanced neuroendocrine tumours (NETs) of the intestine and pancreas when surgery is not
possible
◦ Common side effects
◦ These side effects happen in more than 10 in 100 people (more than 10%). You might have one or more of them. They
include:
◦ Diarrhoea
◦ Tummy (abdominal) pain
◦ Gallstones
◦ severe and sudden tummy (abdominal) pain
◦ yellowing of the skin and the whites of your eyes (jaundice)
HORMONAL AGENTS
PEPTIDE HORMONES
MONOCLONAL
ANTIBODIES
By Maryam gulzar
INTRODUCTION

◦ Monoclonal antibodies are critical tools in many molecular immunology studies. A protein
produced in a laboratory that can bind to specific targets in the body, such as antigens on the
surface of cancer cells.
◦ Many different forms of monoclonal antibodies are utilized in the detection and treatment of
various disorders, including some types of cancer. They can be employed alone or in
conjunction with other agents to deliver medications, poisons, or radioactive substances
directly to cancer cells.
◦ In 1986, orthclone-OKT3 (muromunab-CD3) was the first monoclonal antibody to be
approved for use in preventing kidney transplant rejection.
 Most common MABs includes:
◦ Trastuzumab
◦ Pertuzumab
◦ Bevacizumab
◦ Rituximab
◦ Avelumab
 Majorly there are 3 types of MABs;
1. Antibodies that bind to NGF and inhibit its binding to target cells and its biological activity in culture
(type A);
2. Antibodies that bind to and precipitate NGF but do not inhibit its binding to target cells or its
biological activity (type B);
3. Antibodies that fail to recognize NGF itself, but inhibit nonetheless its binding to target cells (type C).
ANTI-CANCER AGENTS
 Tamoxifen is in a class of medications known as
antiestrogens. It blocks the activity of estrogen (a
female hormone) in the breast. This may stop the
growth of some breast tumors that need estrogen to
grow.
 It usually treat breast cancer that has spread to other
parts of the body in men and women and can
diagnosis of early breast cancer in women who have
already been treated with surgery, radiation, and/or
chemotherapy.
TAMOXIFEN

 Tamoxifen is a tertiary amino compound and a

stilbenoid that derives from a ”hydride” of
a ”stilbene”.
 Chemical formula – C26H29NO
Tamoxifen is a non steroidal SERM of
the triphenylethylene family and was structurally
derived from diethylstilbestrol-like estrogens
and antiestrogens such
as chlorotrianisene and ethamoxytriphetol.
STRUCTURE ACTIVITY
RELATIONSHIP
◦ Alkylaminoethane side chain is important for the antiestrogenic activity.
◦ Para hydroxylation of the phenyl ring on carbon 1 of butene can increase the potency of
antiestrogen.
◦ As the hydroxyl group is present in the equivalent position to the 3-phenolic hydroxyl of 17-
beta-estradiol, 4-hydroxytamoxifen will have very high binding affinity.
◦ Substitution for 4-hydroxytamoxifen appears to be optimal to produce a potent antiestrogen.
◦ The hydroxyl group is critical to locate the alkyl aminoethoxy side chain in the correct
position in the steroid-binding site to block estrogen action.
 Mechanism of action: Tamoxifen competitively inhibits the binding of estrogen to its receptors.
This inhibition is main cause for the activity against the breast cancer cells.
 Common side effects: loss of libido, swelling in feet and ankles, vaginal discharge and hot flashes.
 Therapeutic uses: Adjuvant therapy, Treatment of metastatic breast cancer, Treatment of duc tal
carcinoma.
SYNTHESIS
VINBLASTINE
6-MERCAPTOPURINE
Prepared by ROMICA RASHID
Vinblastine
• Vinblastine is a member of the vinca
alkaloids family of chemotherapy agents.
• Vinblastine was developed from the
Madagascar periwinkle plant.
• This medication is administered
intravenously 
• Molecular Formula
◦ C46H58N4O9
◦ It works by interfering the cell division
THERAPEUTIC USES SIDE EFFECTS

◦ Hodgkin’s Disease ◦ drug may cause a feeling of burning and pain.

◦ testicular cancer ◦ Constipation
◦ bladder cancer ◦ Neurotoxicity
◦ brain tumor ◦ leukopenia
◦ hair loss
Structural Activity Relationship
◦ Aryl or heteroaryl compounds decreases the activity of
the drug.
◦ Strongly polar or charged groups also decreases the
activity of the drug.
◦ Decreasing in the polarity of the substituent produces
more active analogues of the drug.
◦ Decreasing the charge on the substituent also increases
the activity of the analogues of the drug.
◦ The activity of the drug can be restores by the
introduction of the lipophillic liker such as thioether.
◦ Small and uncharged molecules increase the activity
and shows best results.
◦ Mercaptopurine is an antimetabolite
antineoplastic agent with immunosuppressant
properties.
◦ It works by interfering with nucleic acid
synthesis and by inhibiting purine metabolism
uses
Therapeutic uses Side effects

It is used to treat  Common side-effects;

◦ Acute lymphocytic leukemia (ALL),  ◦ yellowing of eyes or skin,
◦ Acute promyelocytic leukemia (APL),  ◦ Dark urine, and painful or difficult urination.
◦ Crohn's disease Serious side-effects;
◦ Ulcerative colitis ◦ Black or tarry stools (melena),
◦ Bloody stools,
◦ Bloody urine
SYNTHESIS OF 6-MP

In the presence of tetraline as a solvent, hypoxanthine is heated along with excess of phosphorous
pentasulfide. These are heated at 200 °C for a few hours.
STRUCTURE ACTIVITY
RELATIONSHIP
◦ The activity of the drug increases with increase in the
carbon chain up to 15-16 carbons, after that, it again
decreases.
◦ Substituent at position 6 which can lead to the
increase in the resonance at 6th position will lead to
increase in the activity of the drug.
◦ Introduction of the hydrophobic substituent at
6th position will increase the activity of the drug.
◦ Substitutions at 2nd position may not change the
activity of the drug, or it may decrease the activity of
the drug depending upon the type of substituent.
At the 6 position the oxo group of
guanine is replace with the thio, amino,
or sulfonyl group ( increase drug activity)
R

At 2 position may be unsubstituted

e.g. (H) in Mercaptopurine., or R
substituted with (F) e.g. Fludarabin R
or (-- NH2) Thioguanine. At 9 position generally unsaturated to give
potent compounds e.g. Mercaptopurine ,
Thioguanine

65
A REVIEW ON FLAVONES
TARGETING SERINE/THREONINE
PROTEIN KINASES FOR
POTENTIAL ANTICANCER DRUGS
Presented by: Shiza Aftab
ABSTRACT
◦ Protein kinases have been important targets for antitumor targets due to their key roles in regulating
multiple cell signaling pathways. Numerous compounds containing flavonoid scaffold as an
indispensable anchor have been found to be potent inhibitors of protein kinases. Some of these
flavonoids have been in clinical research as protein kinases inhibitors. Thus, the present review mainly
focuses on the structural requirement for anticancer potential of flavone derivatives targeting several key
serine/threonine protein kinases. This information may provide an opportunity to scientists of medicinal
chemistry to design multi-functional flavone derivatives for the treatment of cancer.
Introduction
◦ Flavonoids are low molecular weight polyphenolic secondary metabolites derived from plants and play
an important role in numerous biological processes and have always been a focus of life science for
several decades due to their various and vital functions within the cell. Over 9000 flavonoids found in
fruit, vegetables, grains, bark, roots, stems, flowers, tea and wine have been characterized and are
classified into four main groups based on their differences in molecular skeleton: flavones, flavanols,
flavanones, flavanonols, and isoflavones
◦ Flavonoids exhibit diverse biological activities, especially in aspect of anticancer activity through
different mechanisms, such as induction of cell cycle arrest and apoptosis, inhibition of angiogenesis,
disruption of cell migration, and modulation of nuclear receptor responsiveness.
◦ Protein kinases (PKs) are enzymes that catalyze the
phosphorylation of different cellular substrates.
Under pathological conditions, PKs are deregulated,
leading to deregulation of phosphorylation which
leads to uncontrolled cell division, inhibition of
apoptosis, other abnormalities and even malignant
cancers. Fortunately, the flavonoids inhibiting a
number of protein kinases may be a promising
therapeutic strategy against cancer. Since the
approval of Gleevec, U.S. Food and Drug
Administration (FDA) has approved 37 small
molecule protein kinase inhibitors.
Representative flavones as PKC
inhibitors
◦ Protein kinase C (PKC) is a serine/threonine kinase that catalyzes the phosphorylation of the
hydroxyl groups of serine and threonine residues on the cell proteins which plays an important
role in several signal transduction pathways. PKC activated by the tumor promoter may
promote the expression of oncogenes, which is achieved by phosphorylation of transcriptional
activators.
◦ Investigations of a variety of flavonoids as PKC inhibitors, as shown
◦ The results indicate that the flavone luteolin (1) and flavonols fisetin (2) and quercetin (3) are the most potent PKC
inhibitors. Tammela et al. 7 found myricetin (4) as a potent inhibitor of PKC with an IC50 of 7.8 μM. These
compounds are characterized by a 7- hydroxyl benzopyrone ring system with either a 3-or 5-hydroxy substituent and a
3′, 4′-dihydroxy-2-phenyl ring. The flavones apigenin (5) and isorhamnetin (6) with coplanar conformation similar to
quercetin (3) have partial potency. Compared with the most potent PKC inhibitors, apigenin (5) lacks the 3′-hydroxy
group and 3′-hydroxy group of isorhamnetin. (6) is methylated. These may account for their partial potency.
◦ The fact that the flavones nobiletin (7) and tangeretin (8) are inactive also proved this assumption. However,
flavanones such as taxifolin (9) are inactive. Structure comparison shows that the conformational preference of
flavanones is to have a sofa pyran ring with an equatorial phenyl ring twisted about 45° with respect to the
benzopyran ring system,8 whereas flavones such as quercetin (3) are coplanar. This may be the reason why it has
no activity.
◦ The results that the 3-phenyl isoflavonoids are inactive imply that a 2-phenyl flavone is required for
potency. Structure-activity relationship analysis reveals that a planar benzopyrone ring system with a 7-
hydroxy and a coplanar 2-(3′, 4′-dihydroxy)-phenyl ring is required for PKC inhibition by flavonoids, as
shown
DISCUSSION AND CONCLUSION
◦ The strength of flavonoids as protein kinase inhibitors in anticancer drug development is evident from
clinical study of flavopiridol, voruciclib and so on.
◦ Most early kinase inhibitors exhibited poor selectivity between kinases, and the trend in recent years has
been toward ever more selective inhibitors in an attempt to minimize the risk of side effects. The risk
with highly selective inhibitors is that their efficacy for treating complex diseases like cancer might be
compromised by the redundancies in signaling pathways. Very few drugs are truly selective for a single
target. Many clinically useful drugs are now known to have multiple activities. Most of them were
discovered serendipitously and their mechanisms of action were only established retrospectively.
◦ Myricetin is an inhibitor many kinds of protein kinases However, very poor oral bioavailability makes
them largely ineffective in vivo. The low bioavailability is mainly due to limited solubility and highly
efficient glucuronic acid and sulfate conjugation of these mono-or polyhydroxylated agents in the
intestinal/hepatic barrier. Fortunately, the methyl capping of free hydroxyl groups of flavonoids resulting
in increased metabolic stability has been proved. In consideration of the safety of flavonoids, with proper
designing and SAR studies of known flavonoids derivatives, prospective compounds can be designed for
anticancer activity.
REFERENCES
◦ https://doi.org/10.1016/j.bmc.2019.01.027
◦ https://www.ncbi.nlm.nih.gov/books/NBK548022/
◦ https://gpatindia.com/5-flourouracil-5-fu-synthesis-sar-mcqstructuretherapeutic-uses-chemical-property/
◦ https://gpatindia.com/azathioprine-synthesis-sar-mcqstructure-and-therapeutic-uses/
◦ https://gpatindia.com/methotrexate-sar-synthesis-mechanism-of-action-therapeutic-actions-side-effects-
and-mcq/#:~:text=Structural%20Activity%20Relationship&text=Substitution%20at%202nd%2C
%203,the%20activity%20of%20the%20drug.