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

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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

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Mechanism of alkylation: extremely reactive electrophile aziridinium cation

as intermediate

intramolecular SN

monoalkylated

DNA

Dialkylated, cross-linked DNA

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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

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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 !!

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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

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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.

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Chlorambucil Synthesis

protection

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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

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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

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Slower

hydroxylation

3rd line drug !!!

Ifosfamide (IflexTM)

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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

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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

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O6-methylguanine DNA

Triazenes: Dacarbazine (DTICTM)

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Platinum complexes

b

Cisplatin Carboplatin Oxaliplatin

contain an electron-deficient metal

atom that acts as a magnet for

electron-rich DNA nucleophiles

= Matallating agents

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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

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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 )

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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 )

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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 )

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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

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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