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MedChem Midterm 3 > DNA As Drug Targets > Flashcards

DNA As Drug Targets Flashcards

1
Q

Oswald Avery

Franklin

Watson Crick

A

DNA is main constituent of genes

First Xray picture of DNA

DNA Structure

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2
Q

RNA

A
  • Phospho linked polymer of phosphoribose glycosides
  • Has the second -OH group
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3
Q

Purine:

Adenine

A

Has 1 HB acceptor / 1 HB donor

small Arrow shows RIBOSE or DEoxyribose Attachment

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4
Q

Guanine

(purine)

A

2 HB Donor’s /1 HB Acceptor

small Arrow shows RIBOSE or DEoxyribose Attachment

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5
Q

Pyrimidine:

Cytosine

A

2 HB Acceptors / 1 HB Donor

Small arrow shows only DEOXYRIBOSE Attachment

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6
Q

Thymine / Uracil

Pyrimadine

A

1 HB acceptor / 1 HB Donor

Small arrow shows only DEOXYRIBOSE Attachment​

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7
Q

DNA

Details

A
  • NONREDUCING polyglycoside
  • DOES NOT exist in equiibruim with an OPEN chain sugar
  • Depurination process (from drugs / diseases)
    • –> result in equilibrium
      • –> DNA STRAND SCISSION
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8
Q

Why is RNA not a reliable storage medium?

A
  • Typically for DNA, Phosphodiester bond is EXTERMELY resistant to Hydroysis
    • ​half life ~12million years
  • RNA is 1000x faster
    • due to the presence of the 2’-OH group in RNA
      • poised for attack on the phosphorus of 3’ phosphodiester
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9
Q

Structure of Nucleotides

A
  • Nucleotides have B-configuration of the Glycosidic Bond
  • PUCKERED
    • determined by what is bound to the ring
    • destablizing eclipsing steric interactions of substituents on adjacent carbon atom
      • = TORSION STRAIN
        *
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10
Q

Canonical B-Dna

A
  • C2-endo sugar puckers
  • HIGH anti-glycosidic angles
  • 3.4Angstrom helical rise per residue
  • Right Handed (10 base pairs per turn)
  • <15 degree bending
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11
Q

A Form DNA

A
  • C3’s endo puckers
  • Anti glycosidic angle
  • Base pairs TWISTED
  • small helix rise
  • 11 bp per repeat
  • Distinction between MINOR & MAJOR
    • Major groove = DEEP & Narrow
    • Minor grove = WIDE & SHALLOW
  • Larger diameter
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12
Q

Z-Form DNA

A
  • LEFT HANDED HELIX
  • GC-Rich sequences
  • Narrower / most elongated
  • Grooves are NOT well defined
  • Favored by HIGH SALT conc
    • some base subs
    • Needs alternating purine/pyrimidine sequence
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13
Q

Classes of DNA Interactive Drugs

A
  • Reversible Binders
    • ​reversible DNA interactions
  • Alkylators
    • ​react COVALENTLY w/ DNA bases
  • Strand Breakers
    • generate REACTIVE RADICALS that CLEAVE polynucelotide strands
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14
Q

Cancer Cells

A
  • Constantly need DNA & precursers
  • Selective Toxicity
    • Rapid uptake of drug molecules
    • repair mechanisms are too slow
    • activation of proteins such as P53 in normal cells
      • –> response to DNA damage
        • ^dna repair enzymes
        • Cell cycle arrest (time to repair)
        • apoptosis
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15
Q

Combination Chemotherapy

A
  • Compared to a SINGLE drug
    • Able to fight AQUIRED resistance
    • Different MOA’s –> increased effectiveness
    • Covalent modifcations can be REVERSED by repair enzymes
      • Inhibitors of DNA repair can be added
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16
Q

Major Groove

A

Deep & Wide (24Angs)

rich in Basic Atoms

36A x 20A

  • DNA ligands have high specificity to WHICH GROOVE they bind
    • typically poor sequence speficity
    • more specific on which groove
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17
Q

Minor Groove

A

Deep and NARROW (20Angs)

lined w/ HYDROPHOBIC H-atoms of ribose

  1. 4A x 20A
    * Small Molecules (<1000D) bind in minor groove
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18
Q

3 Ways to Reversibly Bind to ​Duplex DNA

A
  • External Electrostatic
    • ​Backbone = Negatively charged (due to phosphodiester groups)
    • –> Charge Interactions w/ charged groups
      • EX. NH3+ ——- (-)phosphodiester groups
  • Groove Binder
  • Intercalation
    • Planar groups slide INBETWEEN
      • ​VDW interactions + Pi Pi stacking
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19
Q

Cis-Platinum

(anti-neoplastic)

A

Covalent = IRREVERSIBLE

Anti-cancer

  • Way that SMALL molecule can bind to DNA
  • Very Stable
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20
Q

3 Ways small molecules can bind to DNA

A

Covalent - Irreversible

cis-plat

Minor Groove Bider

netropsin

Intercalator

dynemyci

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21
Q

Netropsin

A

Minor Groove Binder

Peptide analog Antibiotic (+/- Bacteria)

  • Small molecule that binds to DNA
  • 4 consecutive bases = H-bonding
  • Displaces WATER
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22
Q

Dynemycin

A

DNA Intercalator

Enediyne Anticancer Drug

  • small molecule that binds to DNA duplex
  • Planar Pi Pi Binding
23
Q

Major Groove Dna BInders

A
  • Some might just BIND, –> small or NO EFFECT on structure
    • C2-Repressor
  • Some may cause Major Distortions
    • ​TATA Binding Protein
  • ​Spermine
    • ​binds to DNA by electrostatic forces
24
Q

Methylproamine

A

Minor Groove Binder

Radioprotector / DNA STAIN

  • planar but CURVED to fit in minor groove
25
Q

Minor groove binders

A
  • long / planar / crescent(bent) shaped molecules
  • hydroPHOBIC
    • ​but w/ HB capability to form HB’s w’ DNA bases
  • Most bind to AT-Rich sequences (are where minor groove is NARROWER)
  • AntiMicrobial / AntiTumor activities
  • BOTH Reversible & Irreversable
    • ​Reversible –> prevent access of cell proteins to DNA
    • ​irreversable dmg – > alkylation of bases
26
Q

Platinum Based Anti-neoplastics

Structures & Types

A

Cis-platin / Carboplatin / Oxaliplatin / Phenatriplatin

27
Q

Platinum Anti-neoplastics

MOA

A
  • Covalent Binding –> dGpG-N7 NITROGENS
    • ​form intra-strand crosslink
    • bond to platimum cannot be too LABILE = Toxic
    • nor too strong = low activity
  • Bridges the two bases –> DISTORTION in DNA
    • inhibition of Transcription
    • RNA Polymerase STALLS –> Apoptosis
  • typically carbon –> TETRAHYDRAL
    *
28
Q

Phenanthriplatin

A

7-40 Times MORE POTANT than Cis-Platin

  • result of better Transport & possible intercalation of drug
  • Steven Lippard still develiping the drug for human cancer
29
Q

DNA Alkylators

Examples & Structures

A

Carmustine (BCNU) / Cyclophosphamide / Melphalan

2x -Chlorine

30
Q

DNA Alkylators

A
  • Target DNA by ALKYLATING the DNA Bases
  • Common: Alkylation of GUANINE N-7 (most preferred >N-3 of adenine)
    • generates POSITIVE charge @ nitrogen
    • –> profound hydrolytic instability of glycosidic bond
    • –> DEPURINation & DNA strand SCISSION
  • ​Bifunctional Alkylators –> DNA-crosslinking
    • ​Two bonds on sense / anti-sense
    • Makes them unable to be transcribed
      • ​due to the COVALENT bond
  • NONSELECTIVE = TOXIC
31
Q

Order of NUCLEOPHILICITY

of DNA sites in ALKYLATION RXNS

A

N-7 of guanine > N-3 of adenine

> N-7 of adenine > N-3 of guanine > N-1 of adenine > N-1 of cytosine

*N-3 of cytosine / O-6 of guanine & phosphate groups can also be alkylated

32
Q

MOA of Alkylating Drugs

A
  • Nitrogen Nucleophilicity CRITICAL
  • Unsubstituated mustards = too reactive / toxic
  • EWG substituants (linked to the nitrogen, R group)
    • –> LOWER nucleophlicity/reactivity
33
Q

Negatives of DNA Alkalators

A
  • Can result in MUTATIONS
    • ​–> lead to secondary cancer
    • after the remission
  • Modification can lead to DNA DEPURINation (abasic sites)
    • and/or Strand scission
      • –> trigger DNA repair
      • if attack is too massive, DNA repair can not cope with it.
34
Q

All DNA modifying agents are…

A

Electrophiles

form covalent adducts w/ DNA nuceleophilic sites (bases/phosphodiester groups)

35
Q

DNA Strand Scission by Alkylating Drugs

MOA

A
  • Positive charge on N –> Glycoside break up
  • –> Ribose Hemiacetal (in EQ w/ open chain)
  • –> Open Chain Ribose
  • Beta-Elimination
    • ​strand scission w/ the Phosphate group
36
Q

DNA Supercoiling

Topoisomerases

A

RELIEVES POSITIVE TWISTING

  • Topoisomerase catalyzes the transition of the topological forms of DNA
  • Critical Step = formation of covalent-cleavable complex
    • Attack of active site TYROSINE -OH group on P-group of DNA chain
      • P-O bond Scission
    • Dna has to be RELIGATED to liberate the tyrosine
  • *if this step does not occur
    • topo is IRREVERSIBLY INACTIVATED

​​

37
Q

Actinomycin

A

DNA Intercalator

Antitumor agent

rhabdomyosarcoma and trophoblastic neoplasia​

  • Derived from Streptomyces
  • Stabalizes cleavable complex of topoisomerases
    • ​Cyclic pentapeptide –> aromatic Chromophore
      • via amide bonds (numerous H-bonds)
38
Q

Topotecan-Resistant Topoisomerase 1

A
  • Intercalator comes in and SPLITS the 2 bases
  • Topo Inhibitor prevents the intercalator from releasing
    • ​–> keeps the Nucleic acid from re-joining together
  • Disruption of Topo Catalysis w/ topotecan
    • ​–> stabilization of DNA-Topo adduct
      • & DNA lesion
39
Q

Topo Inhibitors as Drugs

A
  • Topo inhibitors = DNA Intercalators
    • ​But intercalation is NOT sufficient for TOPO inhibitor
    • must also STABILIZE the cleavable topo-dna complex
      • where DNA is covalently linked to TOP-TYR residue
  • Cleavable complex cannot be religated
    • ​due to conformational change imposed on TOPO by inhibitor
      • –> DNA strand breaks that CANNOT be repaired by DNA ligase
40
Q

Doxorubicin

Daunorubicin

Idarubicin

A

Anthracyclin Antibiotics (contain CHROMATIN)

Topoisomerase Inhibitors

  • Common anticancer drugs –>
    • Leukemia / Hodkins Lymphoma / Bladder/breast/lung cancer
  • _​_Limiting factor –> Adverse heart effects
    • ​related to formation of ROS (reactive oxygen species)
  • Antracyclin residue undergoes redox processes
    • –> generation of -OH radical
      • –> can cleave DNA strand
41
Q

Camptothecin

Topotecan

A

DNA Intercalaters that are ALSO TOPO-Inhibitors

in principle MOST DNA intercalators are CARCINOGENS

42
Q

Duocarmycins

A

Minor Groove Binder

activated by conformational change after binding to minor groove

43
Q

Mitomycin

A

Target DNA

Activated by metabolic reduction

44
Q

Dacarbazine

A

Target DNA

activated by P450 hydroxylation

45
Q

Leinamycin

A

Drug that targets DNA

Activated metobolically by reactions with THIOLS

46
Q

Anthracyclins:

Rubicins / Bleomycin / Enidyns antitumor AB’s

A

Hydroxyl Radical Forming drugs

Based from DNA-based radicals

cause DNA Scission / Lesions

47
Q

Thymidylate Synthase Inhibitors

RT inhibitors

Modulators of Epigenic control of DNA Replication

A

Target DNA

Affect DNA SYNTHESIS

48
Q

Antisense Drugs

A
  • Synthetic nuclease-reisistant oligomers of DNA
    • form stable duplexes w/ RNA
    • –> inhibit TRANSLATION of any specific gene
      • ​in principle can be made to treat any disease resulting from gene overexpression
        • by using a proper sequence of nucleobases
  • ​4 drugs have been approved by FDA
    • Etlepirsen (2016)
      • –> treatment of Duchenne muscular dystrophy
  • _​​_Challenges:
    • Drug delivery (high neg charge / MW )
    • very high cost
      *
49
Q

Antisense Nucleotides

A
  • Requirements for an effective antisense oligonucleotide:
    • Form Stable Duplex w/ native DNA/RNA
    • Resist Action of Nucleases
  • ​Modifications to DNA structure:
    • phosphorothiorate analog
    • protection of 2’-OH group of ribose
    • replacement of ribose by morpholino residue
    • removal of negative charge
50
Q

How platin adducts affect DNA fxn?

A

DNA Adduct = segment of DNA bound to cancer causing chemical

Covalently bind to N7 nitrogens –> Intrastrand crosslink

crosslink –> INHIBIT TRANSCRIPTION

–> APOPTOSIS

51
Q

Mono vs BI-functional

DNA Alkylators

A
  • MONO-functional = alkylation –> positive charge on nitrogen
    • ​profound hydrolytic instability
      • –>depurination –> DNA Strand Scission
        • Bi-Functional = TWO bonds on sense and anti-sense
    • Cross-links the two bonds, makes them unable to be trascribed
    • Due to the covalant bond
52
Q

Cyclophosphamide

A

DNA Alkylating Drug

  • Has a NON-NUCLEOPHILIC NITROGEN
    • needs to be metabolicly activated in order to render the Nitrogen nucleophilic
    • = PRODRUG
53
Q

Topoisomerase

A
  • RELIEVE the supercoiling of DNA so that replication could occur
  • Inhibiting TOPO
    • stabilizes the cleavable complex between DNA / TOP
      • –> prevent re-ligation of the excised DNA fragments
      • = anti-cancer drug
  • TOPOs cut DNA strands as part of their catalytic mechanism of relaxation of DNA superhelical state.

MedChem Midterm 3 (7 decks)

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