Anticancer drugs medicinal chemistry 5th semester unit 2 (1)

antineoplastic agents

1. WHAT IS CANCER?

Antineoplastic agents are drugs used for the
treatment of cancer.
Cancer or neoplasm ( Greek neo = new); plasm =

formation ) refers to a group of disease caused by
several agents viz.

Chemical compounds, radiant energy .

Cancer is characterised by an abnormal and
uncontroled division of cells'exhibiting varying,
Degrees of malignancy. which produce tumors and
invade adjacent normal tissue.

2. Often cancer cells separate themselves from
primary tumor and carried by the lymphatic
system, reach distant sites of the organism,
where they divide and form second
tumors(metastasis).

The main characteristics of malignant are,
therefore, (a) autonomous growth , insentive to
the normal control mechanisms that limits cell
growth and division in differentiated tissues and
(b) invasiveness of adjacent capillaries and lymph
channel. ,

3. TYPES OF CANCER

ANAL CANCER ANUS
| BREAST CANCER BREAST =
BLADDER CANCER URINARY BLADDER 1
| BONE MARROW CANCER SHAFTS OF LONG BONES 9
COLON CANCER COLON
CERVICAL CANCER CERVIX 7
| EYE CANCER EYE 7
| GYNAEOCOLOGICAL CANCER FEMALE REPRODUCTIVE ORGANS |
| LUNG CANCER * LUNGS A i
OSTEO SARCOMA ~ METAPHYSEAL REGION OF LONG BONES
| WILMs TUMOUR 7 KIDNEY LE 2 E
LEUKEMIA y BLOOD EZ
LARYNX CANCER . LARYNX -
i pe 7
TESTICULAR CANCER TESTIS
RECTAL CANCER RECTUM =

4. CAUSES AND RISK FACTORS :

Causes of Cancer
1.Environment a, “i E
+ cigarette smoke
e chemicals Infection
e UV light
e viruses

2.Metabolic processes

+ free radicals

e DNA copying and
repair defects

3.Inherited genetic mutations =

5. Classification of Antineoplastic drugs

* Cytotoxic drugs:

+ A. Alkylating agents :

1.Mustard drugs: Mechlorethamine, Chiorombucil, Cyclophosphomide, Melphalan .
2 Aziridines : Thiotepa.

3. Akkylsulphones: Busulphan.

4. Nitrosoureas : Lomustine, Cormustine,
Procarbazine
B. Antimetabolites:
>. Purle antagonists: 6 Mercaptopurine.
Folic acid antagonist: Methotrexate.
Pyrimidine antagonist: 5 Fivorouraci

C. Plant products: 1. Vinka alkaloids
a. Vincristine b. Vinblastine,

2.Taxanes: Paciitaxel, Docetamel.

D. Antiblotics: Dactinomycin, Daunorubicin, Doxorubicin, Mitomycin.
E Radioisotopes: Radlolodine F*, Radiophosphorus P*.
E. Other cytotoxic drugs: Hydroxyurea, cisplatin.

6. CLASSIFICATION OF ANTINEOPLASTIC AGENTS

| There are two Major Groups of Anticancer Drugs:

1. CHEMICAL STRUCTURE AND RESOURCE OF THE DRUG

A) Cytotoxic Drugs (largest group)
-Alkylating agents
-Antimetabolites
-Antitumor antibiotics
- Plant-derived products
Miscellaneous cytotoxic drugs

B) Hormones and hormone antagonists

C) Immunomodulators
-Immunostimulants
-Immunosuppressant

2. CELL CYCLE OR PHASE SPECIFICITY OF THE DRUG
A) Cell cycle non- specific agents(CCNS)
Ex : Alkylating Agents, Platinum Compounds, Antibiotics
B) Cell cycle specific agents:
Drugs that act during a specific phase of the cell cyde
-S- Phase - Antimetabolites , Topoisomerase Inhibitors
-M Phase - Vinca Alkaloids, Taxanes
-G2 Phase — Bleomycin

7. Chemical

ALKYLATING AGENTS

| A) Nitrogen Mustards

-Mechlorethamine
-Cyclophosphamid
-Melphalan |
-Chlorambucil

B) Nitrosoureas
-Carmustine
-Lomustine
-semustine

C) Alkyl Sulfonates

tion of An

ancer Agents

ANTIMETABOLITES

A) Folate antagonist
-Methotrexate

B) Purine antagonist
-6-mercaptopurine
-6-thioguanine
-Azathioprine

| C) Pyrimidine antagonist

-5-Fluorouracil

-Cytarabine

8. HORMONES AND HORMONE

ANTAGONISTS
A) Glucocorticoids
-Prednisolon
-Prednisone
B) Estrogen
-Diethylstilbestreol
C) Anti-estrogen
-Tamoxifen
D) Androgens & Anti-androgens
-Testosteron
-Flutamide
£) Progestin

-Medroxy Progesteron
Acetate

MISCELLANEOUS AGENTS
-Hydroxyurea ( Hydrea )
-Mitotane
-Cisplatin
-Carboplatin
-Mitoxantrone

MONOCLONAL ANTIBODIES

- Trantuzumab
- Rituximab
-Imatinib

9. ANTIBIOTICS
-Actinomycin(D-actinomycin)
-Doxorubicin
-Daunorubicin(rubidomycin)

IMMUNOMODULATORS

A) Levamisole
B) Interferons
-Interferon alfa-2a and 2 b
| C) Interleukins

-Aldesleukin |

PLANT-DERIVED PRODUCTS

A) VINCA ALKALOIDS
-Vincristine
-Vinblastine
B) AXANES

10. The Classification of Anticancer Drugs

A. Drugs acting directly on cells (Cytotoxic
drugs)
1. Alkylating agents:

O These compounds produce highly reactive
carbonium ion intermediates which transfer
alkyl groups to cellular macro molecules by .
forming covalent bonds. eee

o Alkylation results in cross linking/‘abnormal
base pairing/scission of DNA strand.

11. Mechanism of action

Mechanism of action

Alkylating Agents |

Form highly reactive carbonium ion

À

[Transfer alkyl groups to nucleophilic sites on DNA bases

y

mal base pairing

Alkylation also damages RNA

and proteins

12. CLASSIFICATON

CYTOTOXIC DRUGS (directly act on cells)
a) ALKYLATING AGENTS

i. Nitrogen mustards- mustine

ii. Ethyleneimine - thiopeta

iii. Alkyl sulfonate - buslfan
iv. Nitrosoureas - carmustine

v. Triazine - dacarbazine

13. ALKYLATING AGENTS

= Contain chemical groups that can form covalent
bonds with particular nucleophilic substances in
the cell.
Produce highly reactive carbonium
ion intermediates.

Forms covalent bond with electron donors like
amine, hydroxyl and sulfhydryl groups.

Alkylating agents are bifunctional i.c They have
two alkylating groups .

14. = The nitrogen at position 7 (N,) of guanine, being
strongly nucleophilic, is probably the main
molecular target for alkylation in DNA.

= N, and N, of adenine and N, of cytosine may
also be affected.

= Being bifunctional they can cause intra- or

interchain cross-linking, abnormal base
pairing or chain scission.

= Interferes not only with transcription but also
with replication

15. + Main impact is seen during replication (S
phase) when some zones of the DNA are
unpaired and more susceptible to
alkylation.

* Results in a block at G,and
subsequent apoptotic cell death.

16. © Elsevier Ltd. Rang et al: Pharmacology SE www.studentconsult.com

18. Types of Alkylating agents

CATEGORY DRUGS
Nitrogen mustards Cyclophosphamide,
Meclorethamine,
Chlorambucil

Thiotepa
Busulfan
Carmustine, Lomustine

Dacarbazine

19. MECHLOETHAMINE

MOA

1. Attachement of alky gr to DNA bases, resulting in
the DNA being fragmented by repair enzymes in
their attempts to replace the alkylated bases,
preventing DNA synthesis and RNA transcription
from the affected DNA OR
DNA damage via the formation of cross links
which prevents DNA from being separated for
synthesis or transcription. OR

. Induction of mispairing of the nucleotides leading

to mutation.

20. Clinical uses
+ Treatment of hodgkin’s disease

* mycosis fungoides and lymphomas

cl

21. CYCLOPHOSPHAMIDES

MOA

+ It prevents cell division by cross linking DNA
strands

Clinical uses

* Multiple myeloma chronic leukaemias,acute
leukaemia of children, hodgkins disease,lung
cancer

o

Oo...”
RS

22. MEPHALAN

* It alters the DNA nucleotide guanine through
alkylation,causes linkages between strands of
DNA. This chemical alteration inhibite and
RNA synthesis function necessary for cells to

survive.
lo]

'OH
Clas N NH

cl

23. CLINICAL USES
+ Multiple myeloma
« Testicular CANCER

* ovarian cancer

24. BUSULFAN

MOA

* It contain 2 labile methanesulfonate
groups.On hydrolysis the methenesulfonate
gr are released and carbonium ions
produced.

« This carbonium ions alkylate DNA which
results in the interference of DNA replication
and RNA transcription ultimately leading to
the disruption of nucleic acid function.

25. Clinical uses
+ Granulocytic leukaemia

26. CHLORAMBUCIL

MOA

+ induction of mispairing of the nucleoties
leading to mutation.

CLINICAL USES

* chronic lymphocytic
leukaemia,macroglobulinaemia disease.

(CICH,).N > CH,CH,CH,COOH
ww cancerquest org

27. THIOPETA

MOA

+ Alkyl gr of thiopeta is attached to guanine base of DNA
at the number 7 nitogen atom of the imidazole ring.
They stop tumor growth by crosslinking guanine
nucleobases in DNA double helix strands,directly
attacking DNA.
This makes the strands unable to uncoil and separate.
As this is necessary in DNA replication the cells can no
longer divide.

28. Clinical uses
* Chronic lymphatic leukaemia,

+ lymphosarcomatosis,

* carcinoma of breast
N
D>N—P=s
N

29. Synthesis of Chlorambucil

(O 2

4-(4-nitropheny! )butanoic acid

4-Phenyl butyric acid

Pd- CaCO,

pharmawisdom.blogspot.in

FORGES
DS CH¿CH¿CH2COOH ag HN HH. HLEOOH
HOH,CH,C A

HC —— CH
Pd/SOCh, Ethylene Oxide

CIAO
PL CH,CH2CH2COOH
CIH¿CH¿C

Chiorambucil

4-(4-aminophenyDbutanoic acid

2 moles

30. Synthesis of Busulfan

Pyridine
CH;S0,Cl + OH(CH)OH —————g»_—_CH,SO,0(CH,),080,CH
a -2HC1

Methane sulfonyl 1,4-Butanediol Buslulfan

chloride
(2moles)

pharmawisdom.blogspot.in

31. Synthesis of Carmustine

=

Aziridine

0
u) | 2HC] CICH;CH,NH-C—NHCH;CH;CI
—— | Inc | ——— >

+ Ha 0
di(aziridin-1-yl)methanone 1,3-bis-2-chloroethyl urea

COCI,

Phosgene NaNO,

HCOOH

Pharmawisdom.blogspot.in

=0

—Z

Mi uno
0

Carmustine

32. Structures of Alkylating Agents

CIHZCHzC, CH,S0,0(CH,),0S0,CH;
IN CH>CH>CH,COOH
CIH,CH,C bain

Chlorambucil
|
N=0 Naw x
E N
CICH;CH;N—C— NHCH;CH,CI N
II EN
Carmustine Thio-TEPA

o CH,
HH H II /
H,C—N—N—C C-NH-CH_
CH,

Procarbazine

33. SAR OF ALKYLATING AGENTS

»Alkylating agents produce highly reactive carbonium ion intermediates or related
transition complex which transfer alkyl group to cellular macromolecules by covalent
bonds.

“Alkylating agents cross link with carboxyl, hydroxyl, amino, sulfhydryl and phosphate

groups of biomacromolecules results abnorma@base paring/ scission of DNA Stand.

The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA.

*The 7th nitrogen atom of guanine is suitable for formation of covalent bond with
bifunctional alkylating agent

34. E M nr = =
CYCLOPHOSPHAMIDE © a

o
y CH,— CH,—cl
Eu 7 ™ .

SAR: El N cn, — cH,— ci
1. BIS-2- Cyclophosphamide
CHLOROETHYLAMINO A . ww
GROUP IS ESSENTIAL. y ©
2. CHLORO ATOM © SYNTHESIS OF CYCLOPHOSPHAMIDE
PROVIDES MAXIMUM
ACTIVITY.
3. LEVO-ISOMER IS
INACTIVE.
USES: E a ’
1. Multiple myeloma, chronic Iymphocytic ADVERSE REACTIONS: = +
leukemia, Hodgkin's disease, ovarian and lung HAIR LOSS, STERILITY, TESTICULAR
cancer, : ATROPHY, OVARIAN FIBROSIS,

SUPPRESSION OF MENSTRUATION.

35. = Structure activity relation ship:

Aliphatic nitorgen substituent(-CH3)

will push electrons to the amine through

sigma bonds. This electronic enrichment
enhances the Nucleophilic character of the

Jone pair of electrons and increase the

Speed at which the B-carbon of the mustared

will be attacked.

whether the tumor cell or a healthy cell,

the aziridinium ion as soon it forms will react
with cell nucleophiles such as B a

chance of exists for tissue or cell specificity.
which means increased risk of serious side effects
and toxicity.

Nitrogen mustards can decompose in
aqueous media through formation of

the inactive dehalogenated diol.

the oxygen of water can act as nucleophiles
to advance this degradative process.

so buffering solutions to a slightly acidic pH
helps to enhance stability in aqueous solution.

The R group can be either
alipatic or aromatic, is the main
determinant of chemical reactivity
oral bioavailability,and the nature
extent of side effects.

An aromatic N substituent
(Phenyl)group conjugated

mustard nitrogen
will stabilize the lone

pair of electrons through

rosonance.

It slows the intramolecular

nucleophilic attack,aziridinium

ion formation and DNA al
(aromatic mustards have less

side effects and oral administration)
Ex:melphalan,chlorambucil.

here attack of electrophilic beta corbon
is very slow because formation of
aziridinium ion also significantly
delayed. DNA alkylation is controlled
and the drug can be given orally.

36. Some DNA alkylating agents such as nitrogen mustards and nitrosoureas are bifunctional
meaning that one molecule of the drug can bind two distinct DNA bases and DNA
cross-linking through two guanine N’ atoms results.

Nitrogen mustards are bis(B-haloalkyl) amines.

bis- means two; halo (short for halogen) here chlorine.

The 2 chlorine atoms decreases the basic strength of the amino N through a strong
inductive effect.

The unionized amine (two lone pair of electrons) that allows the formation of the highly
electrophilic aziridinium ion.

Mechanism of ation:

The lone pair of electrons on the un-ionized amino group conducts an intramolecular
nucleophilic attack at the B-carbon of the mustard, displacing chloride ion and forms
highly reactive electrophilic aziridinium ion,a quaternary amine salt.

The stained cydic structure are highly electrophilic because of the strong -ve inductive
effectve of the +ve charged N atom.

DNA nucleophile conducts an intermolicular nucleophilic attack which breaks the
aziridine ring and alkylates DNA.

Here guanine is the nucleic acid base involved in the alkylation reaction.

when aziridinium ring cleaves lone pair of electrons are regenerated on mustard nitrogen.
In the same way second arm of the mustard and second molecule of DNA.

Ultimately 2 molecules of DNA(guanine) will be cross-linked through the nitrogen

mustard. mustard's drug hold covalently that's why unable to replicate DNA eventually
cell death is U If this. is RE ke a tumor call the nonin pet as is

37. = SAR of chlorambucil:

This group (bis-ß haloalkyl amine) is bifunctional
(Ane molecule of the durg can bind tow distinct DNA
bases) are very important for chemical reactivity of the drug.

This aromatje’ring is able to stabilize the lone pair of
electrons ón the mustard N through resonance with
conjugated phenyl ring, slowing the formation of reactive
aziridinium ion.

Because the lone pair of electrons of dorambucil and other
aromatic mustards is less reactive,there is a greater
Opportunity for distribution to cancer cells and a decreased
incidence of severe side effects.

38. PURINE SYNTHESIS PYRIMIDINE SYNTHESIS

© Elsevier Ltd ~ et al: mat SE www.studentconsult.com

39. Recent drugs based on Nitrogen
mustard

Q

oR,

Bendamustine

cl
Bestrabucil (phase I trial)
[Chlorambucil derivative] A

-
a e,
+

N *

ASA cite. JH

À

. © Ns

.
Uramustine (Nitrogen mustard+Uracil
EB -

Derivative)

T
a

40. 2. Antimetabolites
Mechanism of actions
o These are analogues related to normal
components of DNA or of coenzymes involved in
nucleic acid synthesis.
o They competitively inhibit utilization of the
normal substrate or get themselves incorporated
forming dysfunctional macromolecules.
o Several of the useful drugs used in
antimetabolite therapy are purines, pyrimidines,

folates, and related compounds. “' -.
© g de

41. ANTIMETABOLITES

= Folate Antagonist. - Methotrexate

= Folates are essential for the synthesis of
purine nucleotides and thymidylate which in
turn are essential for DNA synthesis and cell

division.

« The main action of the folate antagonists is
to interfere with thymidylate synthesis

42. Folate antagonist:

NH2
N. ‘ide f°
vi" wm gnonomeoon
À À 2
HN NAN

COOH

Methotrexate
(NEOTREXATE)

MECHANISM OF ACTION:
«Methotrexate acts an antifolate by binding almost irreversibly to
the enzyme dihydrofolate reductase. >

*Which prevents the formation of the sa oo tetrahydrofolic
acid, essential for replication of animal cells.

+

USES: oy =
Choriocarcinoma, trophoblast tumor and immunosuppressive agents.

e -
Adverse effects:

Megaloblastic anemia, leukemia, diarrhoea, alopecia, intestinal tumour.

43. Purine antagonist

o These are highly effective antineoplastic drugs.
oThey are converted in the body to the
corresponding monoribonucleotides which inhibit
the conversion of inosine monophosphate to
adenine and guanine nucleotides. su

SH
N
ao y
x Ys .
N N = Thioguanjne
6-mercaptopurine USE: Adultacute leukemia

USE: Childhood acute leukemia e

44. « Recent drugs based on purines and related
compounds:

2 NHa NH,
N 7 N ox
ios, DD
cl N Ho o po o
HO

o Si F

HO

HO Clofarabine

Cladribine

45. Pyrimidine antagonist

o Pyrimidine analogues have varied applications
as antineoplastic, antifungal and antipsoriatic
agents. Mechanism of action:

o =5-Fluorouracil is converted in the
body to the corresponding
nucleotide 5-fluoro-2-deoxyuridine
| monophosphate, which inhibits
O N thymidylate synthase and blocks the

conversion of deoxyuridilic acid to
_ deoxythymidylic acid. *

Adenocarcinoma 2
Skin cancer

5-Fluorouracil

This leads to elective failure of DNA
synthesis. >

46. Recent drugs

jo]
lo] H3C(CH2)¿0-C—NH =
F
HN z F
A À | wey
OT N OT N aha
HO. e H3C o Ho
0)
*
OH OH OH
o Floxuridine Capecitabine Tegafur
NH2 NH2 2 NH2
x a 0 NAN NAN
| 1
on on ae e
HO. HO. HO HO.
o O. o) o)
F OH
OH F OH OH OH OH

Cytarabine

47. AZATHIOPRINE

MOA
* It interfere nucleic acid synthesis.

CLINICAL USES

* primary drug used for transplants,especially for
kidney transplants

48. FLOXURIDINE
MOA

+ Catabolized to 5 flurouracil which is the active
form of the drug.

* Primary effect is interference with DNA synthesis

CLINICAL USE

Palliation of gastrointestinal adenocarcinoma
metastatic to the liver in patients

Who are considered incurable
By surgery.

49. CYTARABINE

MOA

* Inhibits DNA synthesis by blocking DNA
polymerase enzyme

CLINICAL USES

+ Acute leukaemia

+ Acute lympholytic leukaemia

* Chronic myclocyctic leukaemia

50. THIOGUANINE

MOA

Interfere the synthesis of guanine nucleotides in
the presence of enzyme inosine monophosphate
dehydrogenase (IMP DEHYDROGENASE)

Clinical uses

* Acute leukaemia ana 7
ER ae

S-Thioguanine

51. METHOTREXATE

MECHANISM OF ACTION

Folic
Acid

| Dihydropteroato synthotase

DHFA Irreversible Inhibition
| OHFA reductase 5]

METHOTREXATE
THFA

| Thymidylate synthase «—ÿ<— |
Partially reversible inhibition

Thymidylate

Purine synthesis

52. Synthesis of Mercaptopurine

> al SCN
H
HN à Pods N N NaSCN NZ N
la | ? Pyridine U | N -NaCl | N
N N Sy N Sy x

Hypoxanthine 6-chloro purine

Pharmawis dom.blogspot.com

Mercaptopurine “*

53. Synthesis of 5-Fluoro Uracil

CF;OF

Fluoroxy trifluro
methane

HN >
Fluorination
A L

o

5-Fluoro uracil

P harmawisdom. blogs pot in

55. 4. Antibiotics

o These are products obtained from
microorganisms and have prominent antitumour
activity.

o Practically all of them intercalate between DNA
strands and interfere with its template function.

Mechanism of action
-binds to double stranded DNA through inter-
Calation between adjacent guanine-cytosine | base
pairs. ,
-Inhibits all forms ‘of DNA- dependent RNA jé an

56. Adverse reaction:

-bone marrow suppression

-sensitizes to radiation, and inflammation at
the sites of prior radiation therapy may occur.

-gastrointestinal adverse effects.

ét
ter a
—N E zu a “9
7 Jay +? Wilms‘ tumour,
\ 2° HN [en
> de = a >) : Rhabdomyosarcoma
JO HNO OW NH 6 A ts
o Y te o.
NA Nito .
Ce 26
Pre

Actinomycin D

57. Recent anticancer antibiotics drugs:

HO, 0
o A 8 = at
RATIO
Bal eof ig"

o” 7 so” OH : \- $e Le]
we] à Ad

9 on 9

Calicheamicin
Oo Nao, ©

HO” FM bs
O 9 OH Y

L - L

Mé OH á

Fostriecin (Preclinical )

58. qe
Me

i

Aoc => Kaposi's sarcoma,
os MA leukemia

> > Carcinomas of the cervix,
7 Breast,lung, stomach
> o +.
. -
$e “

Mitomycin

59. o OH ö
SA;
| À
o 0 OH ll NH
eL),
"OH
i
Doxorubicin
H

OH o HN No

OH O HN ay 0H
E +

Mitoxantrone

Kaposi's sarcoma,
Small cell lung cancer,
Breast cancer,
Malignant lymphomas

Prostate cancer,
Multiple sclerosis

60. BLEOMYCIN

MOA

It chelates copper or iron produces superoxide
ions and intercalates between DNA strand causes
chain scission and inhibite repair

CLINICAL USES
+ Lymphomas
« Carcinomas
« Sarcomas

61. 3. Natural anticancer agents:
Vinca alkaloids

o These are mitotic inhibitors, bind to
microtubular protein-'tubulin', prevent its
polymerization and assembly of microtubules,
cause disruption of mitotic spindle and interfere
with cytoskeletal function.

o The chromosomes fail to move apart during
mitosis: metaphase arrest occurs. - *

o They are cell cycle specific and act in the
mitotic phase.

62. Catharanthine Subunit
AA

: ; COJO

Vindoline Subunit

Hodgkin's disease, N
Acute lymphocytic
leukemia,

Lung cancer

Vinorelbine

63. VINCRISTINE $

MECHANISM OF ACTION: USES:

Mechanism of action *Acute leukemia,
me ee -lymphomas, wilm’s
ka soem tumour, choriocarcinoma.

lagu í

Va > Ye ADVERSE REACTION:

SD a

wi =. Siok, à *Neurotoxicity, areflexia,
ve Da Ae paralytic ileus.

| Xx > ‘
id as meg
o y =

64. The presence of acetyl group is very essential for vinblastine to exhibit it

_ Anti cancer activity. When this is hydrolysed activity gets destroyed.

2. When free hydroxyl grops were acetylated the drug lost its =

_ Antimalignant activity. =
3.The potency of vinblastine reduces pres when the double bonds

Polymerization
nt Are ll he ES

Depolymerization

Tubulin Microtubule

Parent cell

+ Daughter cells

65. © First isolated from bark of
Western / Pacific yew (Taxus
brevifolia)

Uses: It is used for treatment
of lung, ovarian and breast
cancer.

Mechanism of action: Taxanes hyper-stabilizes
microtubule structure (freez them). Taxanes binds to
the B subunit of tubulin ,the resulting microtubule/
Taxanes complex does not have the ability to
disassemble. This adversely affects cell function
because the shortening and lengthening of _
microtubules is necessary for their function. *

66. Ovarian cancer, Breast cancer,
Non —small cell lung cancer

Docetaxel

Semi-synthetic derivatives .

67. Epipodophyllotoxin

Sp pee Uses:small cell lung cancer, Non-Hodgkin's
~ 3; q lymphomas,

Am ag Kaposi's sarcoma, Cervical cancer

From Podophyllum peltarum
May apple
a MOA: Affects DNA

EN topoisomerase Il

o Of = 3 (not intercalating)
UT I DNA strand
= 10 o Zu breakage
= y = O.
mom á |
OMe wot ron . =

Podophyllotoxin Etoposide

68. Camptothecin analogues
o First isolated Camptotheca acuminata

(Chinese tree).
o Inhibits DNA topoisomerase MER) DNA
strand breakage

I ono 1 bd
Camptothecin, - k
toxic, Lead comp. E Topotecan, pe
e y Hycamtin® I
==.
Semisynthetie * .

USES: ovarian cancer, Small cell lung cancer

69. CERATI
MOA

« Prevents cell division by binding to DNA , nuclear
and cytoplasmic proteins causing cross linking

CLINICAL USES

+ Highly reactive with carcinomas of the testicles,
ovaries,heat ‚neck, lungs

Cisplatin

70. MITOTANE
MOA

It modifies the peripheral metabolism of steroids as
well as directly suppressing the adrenal cortex

CLINICAL USE
Treatment of adrenal cortex carcinoma

CI CI
CI

| | CI

71. B. Drugs acting on Hormones

o It involves the manipulation of the endocrine
system through exogenous administration of
specific hormones, particularly steroid hormones,
or drugs which inhibit the production or activity of
such hormones.

o Because steroid hormones are powerful drivers
of gene expression in certain cancer cells;
changing the levels or activity of certain hormones
can cause certain cancers to cease growing, or
even undergo cell death. ” ma

72. ye

1. Corticosteroids :

o Corticosteroids are strong a
e

palliation of lymphom

à , ‘and leukemias, e
eo = ‘
Prednisolone © 2 De
. -

73. 2. Estrogens Xx A
e %

o The agonist is occasionally used to treat
prostate cancer through suppression of
testosterone production.

Fosfestrel 2 .
carcinoma A
prostate

74. 3. ESTROGEN INHIBITORS

o Acts by selective antagonism of the estrogen
receptor.

Say

Al

m con Breast
>
O

Toremifene ° 7

75. 4.Aromatase inhibitors > a

* Aromatase is the enzyme that synthesizes estrogen.

+ Aromatase inhibitors (Als) are a class of drugs used in
the treatment of breast cancer and ovarian cancer in
postmenopausal women.

EXAMPLES:

N
UN

N > '
oa >< Breast cancer
LE Ki oy
NZ “SÁ 7,

Letrozole E «ge .

76. 5. Antiandrogen

*prevent androgens from expressing their biological

effects on responsive tissues.

*Antiandrogens alter the androgen pathway by blocking

the appropriate receptors, competing for binding sites on

the cell's surface, or affecting androgen production.
USES: Antiandrogens are most frequently used to treat
prostate cancer.

; H
O¿N N
N
CH; ES
FC vs

OK +
CH; a Sy

Flutamide