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Title: An ONIOM study of the Bergman reaction: a computational method for modeling enediyne anticancer anti


1
An ONIOM study of the Bergman reaction a
computational method for modeling enediyne
anticancer antibioticsSteven Feldgus George
C. Shields
  • Presented by Kyle Alexander
  • Friday Feb 3rd 2006

2
Enediynes as possible cure for cancer
  • Cancer is a leading cause of death in the United
    States, and enediyne antibiotics may be the cure

Cancer 668,768 22.9
3
Enediyne structure
  • An enediyne is a molecule with a double bond
    between two single bonds, which are adjacent to
    two triple bonds

4
Enediyne family
  • The carbon ring containing the enediyne unit is
    important because it undergoes an electronic
    rearrangement to form a diradical

Dynemicin
Calicheamicin
Esperamicin
Neocarzinostatin
5
DNA (major and minor grooves)
  • The sugar-phosphate backbones surrounds the DNAs
    surface in a spiral pattern.
  • Two different sized grooves are present the
    minor groove is about 50 narrower than the major
    groove.

6
Anti-tumor activity
  • The diradical is positioned in the minor groove
    of DNA, damaging the DNA by abstracting hydrogen
    atoms from deoxyriboses on each strand.

Calicheamicin bound to DNA
Generic molecule bound in minor groove
7
Hydrogen Abstraction
  • The diradical formed from the Bergman reaction
    must bind with DNA so hydrogen abstraction is
    possible

8
Bergman Reaction Cyclization
  • Formation of a new ring in a hydrocarbon chain
  • When enediyne antibiotics target DNA a Bergman
    reaction takes place
  • A biradical reacts with DNA resulting in the
    death of the cell due to DNA scission

2 H-atoms
9
Triggering
  • Importance due its spontaneous effects in natural
    products
  • Trigger is the intramolecular addition which the
    thiol undergoes.

10
Michael Reaction
  • Triggering mechanism takes place during
    bioreductive activation
  • Bergman cyclization produces a diradical which
    kills the cancer cell by hydrogen abstraction
    from DNA.
  • Ring strain is reduced by the change in shape

11
ONIOM
  • ONIOM stands for Own N-layered Integrated
    molecular Orbital and molecular Mechanics
  • Computational technique that combines
    calculations with different levels of theory to
    estimate energy levels of a system
  • Normally includes difficult quantum mechanic (QM)
    calculations along with simpler, but less
    accurate molecular mechanic (MM) calculations

12
Molecular Quantum Mechanics
  • Molecular Mechanics describes motions of bodies
    mathematically to model systems.
  • More classically based (not worried about
    electrons)
  • QM provides accurate and precise descriptions at
    atomic and subatomic levels.
  • QM predicts probability distributions, the
    probability of obtaining each possible outcome
    from measuring an observable.
  • QM is divided into three levels

13
Levels of Quantum Mechanics
  • Hartree-Fock
  • Density Functional Theory (DFT)
  • Coupled Cluster Theory

Increasing electron-electron Interactions
included
Wave-packet in 2-D
14
Feldgus ONIOM method
  • Core and real regions
  • High (cc-pVTZ) and low (B3LYP) levels of theory
  • E(Real High) E(Core High) E(Real Low)
    E(Core Low)

System Studied
Real
Core
15
Enediyne molecules studied
  • Three Benchmark molecules
  • 1) cis-hex-3-ene-1,5-diyne
  • 2) o-diethynylbenzene
  • 3) cyclodec-3-ene-1,5-diyne

2
1
3
16
cyclization
Enthalpic Barrier, ?H
Enthalpy of Reaction, ?Hrxn
Steps of the Bergman Reaction and Corresponding
Energies
17
Benchmark Data
  • Data for Bergman Reaction
  • Enthalpy of reaction (the amount of energy
    absorbed during a reaction, ?Hrxn)
  • Enthalpic barrier (energy needed for reaction to
    take place, ?H)
  • More accurate single point energies are seen from
    the cc-pVTZ theory
  • ONIOM data more accurate than B3LYP 10-25 times
    faster than cc-pVTZ

18
MTC studies
  • Active region (MTC) in calicheamicin and
    esperamicin is almost exactly alike
  • Used as the model system
  • One version with trigger (TR) and another without
    (UT)
  • Study energetics to understand why triggering
    lowers cyclization barrier


19
Effects of Triggering Reaction
  • Two theories
  • Decreased distance between C1-C6 carbons lowers
    the barrier to cyclization
  • Triggering reaction changes ring structure,
    resulting in a lower ring strain energy

20
cyclization
Enthalpic Barrier, ?H
Enthalpy of Reaction, ?Hrxn
Steps of the Bergman Reaction and Corresponding
Energies
21
Energetic Data
  • Shorter C1-C6 distance (3.55 to 3.21 Å ) does not
    significantly lower cyclization barrier
  • Some factor in system, but outside of the core
    must be responsible

22
More Cyclization Barrier Results
  • C1-C6 can not be responsible for cyclization
    barrier because in enediyne 3 C1-C6 distance is
    3.39 ? and barrier is 19.98 kcal/mol
  • This barrier is less than the triggered MTC

2
1
3
23
Negative side effects of enediynes
  • Although having powerful anti-tumor capabilities,
    enediynes also have serious negative side
    effects.
  • Dont distinguish between
  • cancerous cells and healthy cells
  • Cell mutation
  • Cell division
  • Cell death

24
Cell Division
  • In both Mitosis Meiosis DNA replication is a
    crucial step
  • If DNA is changed, the new cells will be
    ineffective or harmful

25
Cell Mutation
  • Mutations are permanent alterations in the
    structure of DNA
  • Possible production of harmful cancer cells

26
Cell Death
  • DNA damage promotes cell death
  • Cell makes a deadly chemical cocktail
  • Separates itself from its neighbors
  • Unleashes poisons which destroy DNA in the cell
    nucleus

A cancer cell (mauve) undergoing apoptosis. Dr
Andrejs Liepins/Science Photo Library
27
Conclusions
  • ONIOM method (B3LYP cc-pVDZ) is an accurate and
    efficient model to study enediyne systems
  • Reduced ring strain, not decreased C1-C6
    distance, is the crucial result of the triggering
    reaction, which lowers cyclization barrier

28
Future Considerations
  • Make enediyne antibiotics which distinguish
    between cancerous and healthy cells
  • Apply ONIOM hybrid theory to other members of
    enediyne family

29
Acknowledgements
  • Dr. Parish
  • Wazo Kristin
  • Kid I kicked out of this room last night
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