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B33CAN - Chemistry > DNA Interactive Anticancer Agents > Flashcards

DNA Interactive Anticancer Agents Flashcards

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1
Q

What is the typical error rate in DNA replication?

A

1 in 10 billion.

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2
Q

What’s the difference between purines and pyrimidines?

A

Purines (bicyclic heterocycles):

  • Adenine (A)
  • Guanine

Pyrimidines (monocyclic heterocycles):

  • Thymine
  • Cytosine
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3
Q

What are alkylating agents? Give examples.

A
  • The alkylating mechanisms just comprises of nucleophilic substitution; but focussing on the attacking group, and not the species with the leaving group
  • Attacking group has a hydrogen (H) replaced w/an alkyl group (e.g. M.E.P.B; methylation, ethylation, propylation, butylation)

E.g.:
• Bendamustine
• Cyclophosphamide

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4
Q

What determines which nucleophilic centres (-ve rich; attacking group) get ‘attacked’ WRT alkylating agents? Common sites of alkylation?

A

Depends on combination of natural chemical reactivity (electronegativity?) and their actual accessibility (major/vs. minor groove of DNA):
- N7 of guanine base (G) is most important target
- N3 of cytosine also common
»> Nitrogens; lone pairs, electronegative; NUCLEOPHILES susceptible to alkylation

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5
Q

What happens to N7 Guanine (and N3 Cytosine) once alkylated?

A
  • Becomes positively charged (Nitrogen now has 4 bonds w/extra alkyl group)
  • +ve charge is resonance stabilised (at N7 guanine AND N3 cytosine)
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6
Q

How do alkylating agents actually exert their anticancer effect?

A
  • Alkylation allows them to bind to DNA (N7 guanine, N3 cytosine)
  • The process of them binding involves nitrogen mustards, allowing chemical cross-linking of DNA strands; permanent covalent bonds, preventing uncoiling and thus DNA replication (transcription cannot occur)
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7
Q

What are nitrogen mustards? How do they result in chemical cross-linking?

A
  • Alkylating agents bendamustine and cyclophosphamide both contain nitrogen mustards
  • (Up to) two chloroethyl groups bound either side to a Nitrogen atom, which is bound to the rest of the alkylating agent (-R)
  • Nitrogen ‘can’t get away’ from nucleophilic site (C - Cl) as it is bonded to it; nucleophilic attack occurs, forming Aziridinium ion (+ve, 3-membered ring with itself, Cl leaving group)
  • Guanine N7 can easily attack the positive Aziridinium ion of the alkylating agents; 3-membered ring unfolds, Guanine N7 now covalently bonded (itself becomes positively charged, is resonance stabilised)
  • Then nitrogen mustard (of bendamustine, cyclophosphamide etc.) is able to form another Aziridinium ion with its other chloroethyl arm, which in turn is attacked by another Guanine N7
  • Resulting in cross-linking of DNA; chemical bridge (nitrogen mustard of alkylating agent) formed between 2 Guanine bases
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8
Q

What is the difference between a monofunctional alkylating agent and a bifunctional one?

A

Monofunctional alkylating agents:
- Contain just one reactive centre (e.g. one chloroethyl arm), can only attack ONE nucleophilic centre (G-N7, C-N3) of DNA

Bifunctional alkylating agents:
- Contain TWO reactive centres (two chloroethyl arms); can react twice with a region of DNA; cross-linking it.

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9
Q

What is the difference between intrastrand and interstrand cross-linking?

A

Intrastrand:
- Formed between two bases that are on the same strand of DNA

Interstrand:
- Formed between one strand of the DNA double helix and the other respective strand (parallel and antiparallel)

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10
Q

What are mutagenic agents?

A

Change the sequence of bases in DNA, but leave overall structure intact.

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11
Q

What are clastogenic agents?

A

Cause deletions, additions or rearrangements to DNA sequence.

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12
Q

What is a lesion?

A

Region of damaged DNA.

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13
Q

What are monoadducts/bisadducts?

A
  • Chloroethyl groups (of nitrogen mustards) that may be hydrated by water instead of forming Aziridinium ion
  • Mono; one chloroethyl; Bi; both chloroethyls (Cl is replaced by OH)
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14
Q

Why is DNA structure distorted in interstrand cross-links?

A
  • Distance between Cls of chloroethyl group of un-Aziridinium’d nitrogen mustard = 5.1 Å
  • Distance normally between guanine nucleobases on opposing strands = 6.8 Å
    »> Thus DNA bends to accommodate cross-link.
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15
Q

How does the alkylating agent cyclophosphamide differ in its action from its fellow alkylating agent, bendamustine? Why?

A
  • Cyclophosphamide itself is not an alkylating agent; it is a pro-drug
  • As the electron-withdrawing phosphoramide group means nitrogen lone pair is not availible for formation of aziridinium ion of nitrogen mustard (drawn into N = P bond instead)
    »> Phosphoramide groups pikeys electron lone pair
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16
Q

How the pro-drug cyclophosphamide bioactivated in the body?

A
  • CYP450-mediated oxidation in the liver to 4-hydroxycyclophosphamide (like TAM is metabolised to 4-OH TAM)
  • 4-hydroxycyclophosphamide is in equilibrium with its ring-opened form, Aldophosphamide (tautomerises)
  • Aldophosphamide undergoes elimination reaction (w/an Acrolein elimination product)
  • Yielding the active phosphoramide mustard, the active alkylating agent
    »> Allows formation of aziridinium ion; phosphoramide group is less electron withdrawing, N still has lone pair for nucleophilic attack of C-Cl to form 3-membered ring
17
Q

What are the common anthracycline antibiotics used in anticancer therapy? What do they share in common?

A
  • Common anthracyclines: Doxorubicin, Daunomycin
  • Both share planar tricyclic aromatic section (making them anthracyclines)
  • Bulky 3D-structure of remaining molecule
18
Q

How do they anthracyclines exert their anticancer effect?

A
  • DO NOT form covalent bonds like alkylating agents
  • Interact non-covalently w/DNA instead; planar anthracycline rings insert between the planes of successive base pairs; INTERCALATION
  • Intercalation process itself is not cytotoxic; it inhibits the actions of Topoisomerase (II in Doxorubicin + Daunomycin, ) enzyme, inhibiting the religation of the cut section of DNA (final step of the enzyme mechanism)
    »> Ultimately producing double strand breaks in the DNA
19
Q

Why are Topoisomerase enzymes required in the DNA replication process in the first place? What’s the difference between TI and TII?

A
  • As DNA unwinds for replication (transcription); twisting tension builds-up in the rest of the supercoil
  • To keep unwinding DNA, tension needs to be released; topoisomerase enzymes cut DNA strands then splice them back together after
    > Topoisomerase I; cuts a single strand of the ds double helix, passes the other strand through the cut, then reseals break (overall strand has one fewer twist, relaxing DNA)
    > Topoisomerase II: cuts both strands of double helix, passes another double strand through, and then reseals the break (relieves tension from unwinding DNA - removes supercoil 2 twists at a time)
20
Q

How does etoposide work? What therapeutic target does it share?

A
  • Etoposide (for testicular cancer; salty sodium salicylate added to counter solubility issues) binds to Topoisomerase II complex, leading to formation of DNA ds-breaks (preventing re-ligation)
  • Just like the Topoisomerase II inhibitor, Doxorubicin
    »> But is NOT an anthracycline antibiotic; has no extended planar tricyclic aromatic ring section, does NOT intercalate into DNA (diff. mechanism)
21
Q

How do platinum-based compounds work? Give examples.

A
  • Bond covalently to DNA via their platinum ion, Pt.
  • Both links to DNA are made through the SAME Platinum ion; nucleophilic centre attached must be close to each other
  • Forms interstrand AND intrastrand cross-links
  • Common if two nucleophilic centres are on adjacent bases of the same strand of DNA; forming a 1, 2 intrastrand cross-link
22
Q

What is Topotecan derived from? What does it act on?

A
  • Derived from camptothecins
  • Topoisomerase I inhibitor
  • Topotecan is the semi-synthetic analogue that is clinically useful
23
Q

How is Topotecan clinically usefully compared to the naturally derived product, camptothecin?

A
  • Dimethylamino group (side chain) of Topotecan is protonated at physiological pH
  • This increases polarity of Topotecan and its water solubility, therefore bioavailability
  • Topotecan -OH group also increases polarity
24
Q

Give examples of some DNA damaging agents.

A
  • Sunlight (UV)
  • Ionising radiation (radon, potassium)
  • Bioactive chemicals in the environment/diet
  • By-products of metabolism (ROS)
  • Errors in DNA replication

B33CAN - Chemistry (4 decks)

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