antineoplastic agents - 112.133.209.26:82
TRANSCRIPT
GURU NANAK INSTITUTE OF PHARMACEUTICAL SCIENCE
& TECHNOLOGYSODEPORE, KOLKATA- 700114, WEST BENGAL, INDIA
MAKAUT AFFILIATED , AICTE & PCI APPROVED, NAAC AND NBA ACCREDITATED
Dr. Sumana Chatterjee
Professor
ANTINEOPLASTIC AGENTS(PART - II)
PT513B: MEDICINAL CHEMISTRY II
B. PHARM THIRD YEAR, SEMESTER - 5
SESSION: 2020-21
Email: [email protected]
MEDICINAL CHEMISTRY II: PT513B
Credit: 4CO LABEL CO STATEMENT BTL
CO513B.1 Classify the therapeutic agents and outline the synthetic route
for the selective medicinal compounds of each category2
CO513B.2 Articulate on the mechanism of action of agents acting on
autonomous and central nervous system.3
CO513B.3Compare the relationship between the biological activity and
structure of therapeutic agents.6
CO513B.4Outline the rational use of Histamine receptor antagonists,
antibiotics, antineoplastic and antidiabetic drugs4
Department of Pharmaceutical Chemistry; Guru Nanak Institute of Pharmaceutical Science and Technology
TOPIC: ANTINEOPLASTIC AGENTS
Teaching Learning Objective (TLO) CO LABEL BTL
To explain neoplasia and classification of tumor CO:PT513B:1 2
To explain different treatment approaches of cancer CO:PT513B:1 2
To explain cell cycle and check points and etiology of cancerCO:PT513B:2 3
To explain Chemical Structure, Category, Use and mode of action of the following:
i.Mechlorethamine ii. Melphalan iii. Cyclophosphamide
iv. Chlorambucil v. ThioTEPA vi. Busulfan
CO:PT513B:4 4
Department of Pharmaceutical Chemistry; Gurunanak Institute of Pharmaceutical Science and Technology
LECTURE I
Definition, types and Characteristics of Tumor
Classification of Cancer on the basis of origin
Stages of Cancer and Treatment Approaches
Cell Cycle and Checkpoints
Apoptosis
Etiology of Cancer
LECTURE II
Mechanism of Alkylating Agents
Classification of Alkylating Agents
Chemical Structure, Category, Use and mode of action of the following:
Mechlorethamine Melphalan Cyclophosphamide Chlorambucil ThioTEPA Busulfan
MEDICINAL CHEMISTRY II: PT513B
TOPIC: AntiNeoplastic Agents (Part I)UNIT –I
PRE_REQUISITE
Fundamental knowledge about
• Physiology
• Biochemistry,
• Organic chemistry
• Drug receptor interaction
• Significance of drug
development
Alkylating Agents
• The alkylating agents are capable of forming covalent bonds with important biomolecules.
• The major targets of drug action are nucleophilic groups present on DNA, proteins and RNA.
• In DNA, the alkylating agent frequently forms either intrastrand or interstrand cross links to inhibit transcription.
• In RNA, only intra-strand cross links are possible.
• Alkylation of DNA is thought to lead to cell death.
• Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the
template function of DNA.
• There are several potential nucleophilic sites on
DNA, which are susceptible to electrophilic
attack by an alkylating agent:
Guanine: N-2, N-3, and N-7
Adenine: N-1, N-3
Thymine: O–6
Cytosine: N-3
MEDICINAL CHEMISTRY II: PT513B
The general mechanism for alkylation involves
Nucleophilic attack by –N=, -NH2, -OH, - O-PO3H of DNA and RNA while additional nucleophiles (-SH,
COOH, etc.) present on proteins may also react.
Anion formation increases the reactivity of the nucleophile compared with the un-ionized form (-O is more
nucleophilic than OH).
Reaction with water is also possible.
Reaction involves displacement of a leaving group on the electrophile by the nucleophile.
• Alkylation converts the base to an effective leaving
group.
• Altered base pairing away from the normal G-C: A-T
hydrogen bonds because of alterations in
tautomerization.
• The alkylation also leads to increased acidity of the N-1 nitrogen reducing the pKa from 9 to 7 to 8 giving rise to a
zwitterionic form that may also mispair
The alkylating
agents are are not
cell cycle–
specific agents.
MEDICINAL CHEMISTRY II: PT513B
Alkylating Agents
Nitrogen Mustard
Alkyl Sulfonates
Nitrosourea
Triazines
Platinum Containing
Ethyleneamine & Methyleneamine
Derivatives
Mechlorethamine, Cyclophosphamide,
Ifosfamide, Melphalan and Chlorambucil
Altretamine, ThiotepaBusulfan
Carmustine, Lomustine
Dacarbazine, Procarbazine, TemozolomideCisplatin, Carboplatin, Oxaliplatin
MEDICINAL CHEMISTRY II: PT513B
NITROGEN MUSTARDS
The nitrogen mustards are compounds that are
chemically similar to sulfur mustard or mustard gas
developed and used
in World War I.
They used to produce blisters as black mustard
seeds produce on exposure to the oil.
Sulfur Mustard is gas at room temperature.
Conversion of the sulfide to a tertiary amine resulted nitrogen mustards, which exist as solids at room The term
mustard was then Mustards such as mechlorethamine are classified as dialkylating agent.
A weakly electrophilic b-carbon atom of an aliphatic nitrogen mustard alkylating agent, such as mechlorethamine
(Mustine) is converted to more highly electrophilic aziridine anion by internal nucleophilic substitution b- Chlorine
atom.
Aziridine
MEDICINAL CHEMISTRY II: PT513B
Nucleophilic attack on N7 of guanine residue can then occur at the aziridinium carbon by an SN2 reaction type of
mechanism to relieve the small ring strain and neutralize the charge on nitrogen.
This process can then be repeated provided a second leaving group is present.
Mechlorethamine is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for oral
administration and necessitating direct injection into the tumor.
The antidote sodium thiosulfate (Na2S2O3), a strong nucleophile, may be administered in case of extravasation.
Mechlorethamine
Significant Limitation of
Mechlorethamine
Lack of selectivity
Aziridinium ionMEDICINAL CHEMISTRY II: PT513B
Approaches To Overcome the Limitation
• Replacement of the weakly electron-donating methyl group with groups that were
electron withdrawing (-I).
• Attachment of nitrogen to a phenyl ring in the case of chlorambucil and melphalan.
Melphalan Attachment of the mustard functionality to a phenylalanine
moiety was not only an attempt to reduce reactivity but
also an attempt to increase entry into cancer cells by
utilization of carrier mediated uptake.
Melphalan was found to utilize active transport to gain
entry into cells, but selective uptake by cancer cells has
not been demonstrated.
Cyclophosphamide
Attachment of more highly electron-withdrawing phosphoryl function
does not allow aziridinium cation formation until the electron- withdrawing function
has been altered.
The drug could be selectively activated in cancer cells because they were believed to
contain high levels of phosphoramidase enzymes. This would remove the electron-
withdrawing phosphoryl function and allow aziridine formation to occur.
Melphalan
Cyclophospamide
MEDICINAL CHEMISTRY II: PT513B
• Cyclophosphamide is activated by cytochrome P450 to give a carbinolamine which undergo ring opening to
give the aldehyde.
• The increased acidity of the aldehyde -hydrogen facilitates a retro-Michael decomposition.
• The ionized phosphoramide is now electron-releasing via induction and allows aziridinium cation formation to proceed.
• Acrolein is also formed as a result of this process, which may itself act as an electrophile that has been associated with
bladder toxicity.
• Alternatively, the agent may be inactivated by alcohol dehydrogenase–mediated oxidation of the carbinolamine to give
the amide or by further oxidation of the aldehyde intermediate to give the acid by aldehyde dehydrogenase.
• To decrease the incidence of kidney and bladder toxicity, the sulfhydryl (MSH) containing agent mesna may be
administered and functions to react with the electrophilic species that may be present in the kidney.
Use & Dosage Forms of Mephalan
Melphalan is available in 2-mg tablets and 50-mg vials for
oral and IV administration in the treatment of multiple
myeloma, breast and ovarian cancer, and in high dose therapy
when bone marrow transplant.
Use & Dosage Forms of Cyclophosphamide
Cyclophosphamide is available in 25- and 50-mg tablets
for oral administration and 100-, 200-, 500-, 1,000-, and
2,000-mg vials for IV use in the treatment of breast
cancer, non-Hodgkin’s lymphoma, chronic lymphocytic
leukemia, ovarian cancer, bone and soft tissue sarcoma,
rhabdomyosarcoma, neuroblastoma, and Wilms tumor
MEDICINAL CHEMISTRY II: PT513B
Chlorambucil
UsesFor treatment of
• Chronic lymphatic (lymphocytic) leukemia
• Childhood minimal-change nephrotic syndrome
• Malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's
lymphomas
Mechanism of Action
Alkylating agents work by three different mechanisms:
Attachment of alkyl groups 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.
DNA damage via the formation of cross-links (bonds between atoms
in the DNA) which prevents DNA from being separated for synthesis
or transcription.
Induction of mispairing of the nucleotides leading to mutations.
Chemical Name: 4-(p-bis(β-chloroethyl)aminophenyl)butyric acid
Dosage Forms Available:
2-mg tablets for oral administration in combination with prednisone and
as a single agent.
Adverse Effects include
o Dose-limiting myelosuppression
o Nausea and vomiting occur less often than
for mechlorethamine.
o Additional adverse effects include
hyperuricemia, azoospermia, amenorrhea,
seizures, pulmonary fibrosis, and skin
rash.
ChlorambucilMEDICINAL CHEMISTRY II: PT513B
• Thiotepa contains the thiophosphoramide functionality.
• Thiophosphoramide functionality is more stable than the
oxa-analog N, N′, N′′-triethylenephosphoramide (TEPA).
• It is metabolically converted to TEPA by desulfuration in
vivo.
• Thiotepa incorporates a less reactive aziridine ring
compared with that formed in mechlorethamine.
• The adjacent thiophosphoryl group is electron withdrawing
and, therefore, reduces the reactivity of the aziridine ring
system.
Thiotepa
• Although thiotepa is less reactive than many other alkylating agents, it has been shown to form cross-links.
• TEPA undergoes hydrolysis to give aziridine, which may function to monoalkylate DNA.
• The reactivity of aziridine generated by either route may be somewhat enhanced within cancer cells, where the pH is
normally reduced 0.2 to 0.4 pH units resulting in an increase in reactivity toward nucleophilic attack.
MEDICINAL CHEMISTRY II: PT513B
Mechanism of Action
• The alkyl group is attached to the guanine base of DNA, at the
number 7 nitrogen 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.
• These drugs act non-specifically.
Uses
Thiotepa is used to treat cancer. It works
by slowing or stopping the growth
of cancer cells.
Thiotepa is often given into the bladder to
treat bladder cancer.
Thiotepa is also used with other
medications to prevent rejection of a stem
cell transplant.
Dosage Forms of Thiotepa
Thiotepa is available in 15-mg vials for IV administration in
the treatment of bladder cancer, ovarian cancer, and breast
cancer.
MEDICINAL CHEMISTRY II: PT513B
Busulfun
• Busulfan utilizes two sulfonate functionalities as leaving groups separated by a
four-carbon chain that reacts with DNA to primarily form intrastrand
cross-link at 5-GA-3 sequences.
• The sulfonates are also subject to displacement by the sulfhydryl functions
found in cysteine and glutathione, and metabolic products are formed as a result
of nucleophilic attack by these groups to generate sulfonium species along with
methane sulfonic acid.
• This is followed by conversion to tetrahydrothiophene, and further oxidation
products are subsequently produced to give the sulfoxide and sulfone.
• The cyclic sulfone known as sulfolane may be further oxidized to give 3-
hydroxysulfolane
Busulfan
MEDICINAL CHEMISTRY II: PT513B
Uses & Dosage Form
Busulfan is available as 2-mg tablets for oral administration and
10-mL vials for IV administration in the treatment of chronic
myelogenous leukemia (CML) and in high-dose
therapy for refractory leukemia with bone marrow transplant.
Adverse Effects
Myelosuppression, nausea and vomiting
pulmonary symptoms including interstitial
pulmonary fibrosis, mucositis, skin rash,
impotence, amenorrhea, infertility,
hepatoxicity, insomnia, anxiety, and an
increased risk of secondary malignancies.
Mechanism of Action of Busulfun
MEDICINAL CHEMISTRY II: PT513B
REFERENCES
• John M. Beale, Jr & John H. Block (Eds) (2006). Wilson and Giswold’s Text
Book of Organic medicinal and Pharmaceutical Chemistry, London, Lippincott
William & Wilkin.
• Thomas M Lenke & David A Williams (Eds ) (2007). Foyes Medicinal
Chemistry, London, LEMKE, Wolters Kluwer & Lippincott Williams and
Wilkins.
Next Topic:…………. Antineoplastic Agents (Part III)
……. Antimetabolites
Department of Pharmaceutical Chemistry; Gurunanak Institute of Pharmaceutical Science and Technology