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PHARMACEUTICAL CHEMISTRY II
(PHCM672)
Lecture 9, ANTICANCER AGENTS II
Alkylating agents and platinum complexes
Dr. Mohammad Abdel-Halim
Anticancer Drugs 1) Antibiotics
2) Alkylating agents and platinum complexes
Alkylating agents A) Nitrogen mustards B) Busulfan C) N-Nitrosoureas D) Triazenes
Organoplatinum complexes Cisplatin Carboplatin Oxaliplatin
3) Topoisomerase Inhibitors
4) Antimitotic agents
5) Signal transduction inhibitors
6) Antimetabolites
7) Miscellaneous
8) Hormones based therapies Pharmaceutical Chemistry 4
3
Alkylating Agents
a
A) Nitrogen mustards B) Busulfan C) N-Nitrosoureas D) Triazenes
Drug
Alkylating Agent
DNA
Protein
Drug
Alkylating Agent
DNA
Protein
Cell
Death
Covalent
bond
Cytotoxicity
Alkylating
agents Highly electrophilic compounds that
react with nucleophilic groups on
DNA to form strong covalent bonds.
DNA-Nuc-H + R-X Alkylation
DNA-Nuc-R + H+ + X-
X=leaving group
5
Alkylation of guanine at N7 and subsequent depurination of DNA
Nucleophilic sites on DNA
Drug
E
Nu
6
Chemically similar to mustard gas (sulfur mustard)
used in WWI as chemical weapon → burns and blisters
of the skin and lung tissue
Possesses antineoplastic properties, mutagenic,
cancirogenic
Mechanism of toxicity: DNA-alkylation
Highly lipophilic easily penetrating skin
Sulfonium cation,
strong electrophile
A) Nitrogen Mustards
mustard gas
2- Melphalan
1- Mechlorethamine
3- Chlorambucil
4- Cyclophosphamide
5- Ifosfamide
Nitrogen mustards were designed from sulfur mustard by S
→ N exchange
X = alkyl, aryl,
A) Nitrogen Mustards
either aliphatic or
aromatic, it is the
prime determinant
of chemical
reactivity, oral
bioavailability, and
the nature and
extent of side effect
Mechlorethamine HCl (MustargenTM)
Used as hydrochloride to increase water solubility
Extreme high reactivity
→ rapid and non-selective alkylation of cellular nucleophiles
→ excessive toxicity (see the next slide)
The high reactivity makes oral administration impossible → iv
administration or direct injection into the tumor
pKa 6.1 (electron withdrawing Cl atoms) → ~ 5% ionization at pH 7.4
Aziridinium
“Highly reactive” E
= DNA
Mechanism of DNA alkylation
intramolecular SN
Mechlorethamine HCl (MustargenTM)
The intra- and intermolecular reactions happen so rapidly that almost
no chance exists for tissue or cell specificity, which means a greatly
increased risk of serious side effects and use-limiting toxicity
Comapred to the other drevatives, mechlorethamine nitrogen is the
strongest base (→ strongest nucleophile N) fastest generation of
Electrophilic Aziridinium cation
10
Mechanism of alkylation: extremely reactive electrophile aziridinium cation
as intermediate
intramolecular SN
monoalkylated
DNA
Dialkylated, cross-linked DNA
11
Inactivation by sodium thiosulfate Na2S2O3
- severe nausea and vomiting
- myelosuppression (lymphocytopenia and granulocytopenia)
- alopecia
- mutagenic/cancerogenic effects on bone marrow stem cells
→ extended use can cause myelogenous leukemia
Side
effects:
→ very limited use, combination therapy to treat cancers of blood
Mechlorethamine HCl (MustargenTM)
It is a severe vesicant, and if accidental skin contact occurs, the drug must
be inactivated with 2% sodium thiosulfate (Na2S2O3) solution.
Antidote
12
The lack of selectivity of mechlorethamine led to attempts
to improve on the agent. One rationale was to reduce the
reactivity by reducing the nucleophilicity of nitrogen,
thereby slowing aziridinium cation formation. This
could be accomplished by replacement of the weakly
electron-donating methyl group with groups that were
electron withdrawing.
DNA
Protein
….etc
Fast
Check the coming drugs !!
13
Chlorambucil (LeukeranTM)
Aromatic amines → weaker baseic N and nucleophilic N than
mechlorethamine → slower formation of the E aziridinium cation
More stable, orally active tablets, also iv administration
Lower incidenece of nusea and vomiting and lower potential of
myelosupression
Melphalan: phenylalanine analog with increased entry into the cancer cells
using aminoacid transporters
Melphalan (AlkeranTM)
phenyl alanine phenyl butyric acid
14
Slower formation of
aziridinium cation
Mechlorethamine
Melphalan and chlorambucil
Mechlorethamine forms Aziridinium faster, thus more reactive
lone pair more
available
Aromatic mustards have a reactivity
sufficiently controlled to permit oral
administration and attenuate the severity
of side effects.
15
Chlorambucil Synthesis
protection
16
Attachment of more highly electron-withdrawing
functionalities was utilized in the case of
cyclophosphamide and ifosfamide. In these cases,
aziridinium cation formation is not possible until the
electron-withdrawing function has been altered, So they
are prodrugs need metabolic activation
cyclophosphamide ifosfamide
Cyclophosphamide (CytoxanTM)
Mustard ‚‘‘Bis-(chloroethyl)amine‘‘ unit is a part of phosphoric acid
amide → reduced N-nucleophilicity
Chiral phosphorus atom, used as racemic mixture
Orally active (oral bioavailability 75%), t1/2 = 3-12 h
Prodrug activated in the liver by CYP450 (CYP3A4, CYP2B6)
*
the most commonly
used alkylating agent
in cancer
chemotherapy
Cyclophosphamide (CytoxanTM)
ionised
19
Coadministration with an adjuvant MESNA (sodium 2-mercaptoethane sulfonate)
reduces kidney and bladder toxicity associated with acrolein
Relatively little bone marrow, liver, and intestinal epithelium toxicity because of high
conc. of aldehyde dehydrogenase in these tissues
Nephrotoxicity can be prevented by adequate fluid intake and mesna
β
α
Antidote
Ifosfamide (IflexTM)
Slower hydroxylation (particularely for the S-isomer)
→ 3-fold higher doses required for equall antineplastic action
Major pathway: dechloroethylation → high conc. of nephrotoxic ClCH2CHO →
higher nephro- and neurotoxicity (can not be prevented by mesna)
iv administration to treat testicular and other solid and soft-tissue
cancers
Common toxicity: cerebral neuropathy (caused by ClCH2CHO in CNS)
Metabolic differences to cyclophosphamide: See the next slide
Cyclophosphamide isomer
(iso-fosfamide), relocation of one chloroethyl
group to the ring nitrogen
Cyclophosphamide is safer and more potent
21
Slower
hydroxylation
3rd line drug !!!
Ifosfamide (IflexTM)
22
Busulfan (MyleraneTM)
Alkyl sulfonate, ester of
1,4-butandiol and methylsulfonic acid
Monoalkylation and cross-linking of DNA possible, mainly through N7 of guanine
Reactions with Cys-SH and
GSH possible
Oral or iv treatment of chronic
myelogenous leukemia (CML)
SN2
methylsulfonate (mesylate)
good leaving group
Unstable agents decomposing non-
enzymatically at lower and higher pH to
isocyanate and strongly electrophilic
chloroethyl carbocation
N-Nitrosoureas
urea
nitroso
group carbamoyl
24
Lomustine (CCNUTM) and Carmustine (BiCNUTM)
N-(2-chloroethyl)-N´-cyclohexyl-
N-nitrosourea N,N´-Bis-(2-chloroethyl)-
N-nitrosourea
Oral administration
Extensive hepatic metabolism
(cyclohexane hydroxylation,
denitrosation, dechlorination)
Dose-limiting myelosuppresion
Highly lipophilic drugs indicated for use in brain tumors and Hodgkin´s disease
iv administration (10% ethanol to
improve solubility)
Available as biodegradable discs that
are implanted under the skull
Rapid metabolism, t1/2 = 20 min
(nonenzymatic decomposition,
denitrosation, dechlorination)
myelosuppresion and pulmonary toxicity
Carmustine Lomustine
methylate guanine via diazomethane and/or methyl carbocation
methyl-triazene group: -N=N-N-CH3
Dacarbazine
Triazenes: Dacarbazine (DTICTM)
Triazene
Resistance: cancer cells produce O6-methylguanine-DNA-
transferase demethylating guanine
iv treatment of malignant melanoma
26
O6-methylguanine DNA
Triazenes: Dacarbazine (DTICTM)
27
Platinum complexes
b
Cisplatin Carboplatin Oxaliplatin
contain an electron-deficient metal
atom that acts as a magnet for
electron-rich DNA nucleophiles
= Matallating agents
28
Organoplatinum Complexes
Anticancer action discovered by serendipity (Rosenberg, 1965)
→ Pt-electrodes were used in experiments investigating the influence of
electric current on cell-division of E. coli bacteria in NH4Cl solution
→ Octahedral cis PtCl4(NH3)2 complex was found to be the active species
(trans isomer was not active)
→ Square planar cis PtCl2(NH3)2 complex turned out to be more effective
and supressed tumors in rats
Carboplatin oxaliplatin Cisplatin
Pt(II)-complexes with square planar geometry
29
Cis-diamminodichloroplatinum(II)
Relatively stable in the blood circulation due to rel. high [Cl-]
Activated after entering the cell (low [Cl-] !) by aquation → the
positively charged diaqua-complex is trapped in the cell
intrastrand cross-linked
DNA
Plasma t1/2 < 30 min (fast hydration)
Cisplatin (Plationol-AQTM,DDPTM )
30
Strong protein binding (terminal elimination t1/2 5-10 days)
iv treatment of metastatic testicular and ovarian cancer, and bladder cancer
In addition to myelosuppression, cisplatin is highly nephrotoxic,
emetic, and ototoxic: 1) Highly nephrotoxic (reduced dosage for patients who take other nephrotoxic
drugs, such as cyclophosphamide or with pre-existing kidney disease
→ Protection against kidney damage:
- drinking chloride-containing solutions
- sodium thiosulfate (accumulates in the renal tubules)
2) Severe emetogen (strong vomiting) → coadministration of antiemetiic
Cisplatin (Plationol-AQTM,DDPTM )
31
3) Ototoxic (irreversibly hearing loss)
→ Coadministration of amifostine desreases toxicity, particularely
ototoxicity
React with Cis platin
Antidote
Mechanism of resistance by cancer cells: decreased uptake,
increased inactivation by SH-containig proteins, increased DNA
repair by mismatch repair enzymes (MMR)
amifostine
Cisplatin (Plationol-AQTM,DDPTM )
32
Carboplatin (Plationol-AQTM,DDPTM )
Activated as cisplatin by aquation
Contains a chelating 1,1-cyclobutane-
dicarboxylate → 10-fold slower rate of
aquation than for cisplatin
(plasma t1/2 = 3 h) → ~ 30-times less potent
anticancer agent than cisplatin
→ reduced nonhematologic toxicity (emesis, nephrotoxicity and
ototoxicity are rare)
Dose-limiting side-effect : myelosuppresion
Less extensive binding to plasma proteins (terminal elimination t1/2
2-6 h)
Approved for treatment of advanced ovarian cancer
Unlabeld uses for lung, head, and neck cancers
Shows cross-resistance with cisplatin
33
Oxaliplatin (EloxatinTM )
Contains a chelating oxalate and 1,2-transdiamionocyclohexane (trans- DACH)
activation by aquation
Does not show cross-resistance with cisplatin and Carboplatin :
bulkier agent causing more extensive DNA-binding that can not be “repaired“
by MMR enzymes
Strong protein binding (terminal elimination half-life 240 h*) .
* time needed to totally remove 50% of the drug from the body
Less nephrotoxic, hematotoxic, and ototoxic than cisplatin
Peripheral neuropathy caused by Ca2+-chelatation with oxalate
Treatment of colon and rectal cancer
Oxaliplatin
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Thank You