Title: An ONIOM study of the Bergman reaction: a computational method for modeling enediyne anticancer anti
1An 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
2Enediynes 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
3Enediyne structure
- An enediyne is a molecule with a double bond
between two single bonds, which are adjacent to
two triple bonds
4Enediyne family
- The carbon ring containing the enediyne unit is
important because it undergoes an electronic
rearrangement to form a diradical
Dynemicin
Calicheamicin
Esperamicin
Neocarzinostatin
5DNA (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.
6Anti-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
7Hydrogen Abstraction
- The diradical formed from the Bergman reaction
must bind with DNA so hydrogen abstraction is
possible
8Bergman 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
9Triggering
- Importance due its spontaneous effects in natural
products - Trigger is the intramolecular addition which the
thiol undergoes.
10Michael 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
11ONIOM
- 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
12Molecular 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
13Levels of Quantum Mechanics
- Hartree-Fock
- Density Functional Theory (DFT)
- Coupled Cluster Theory
Increasing electron-electron Interactions
included
Wave-packet in 2-D
14Feldgus 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
15Enediyne 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
16cyclization
Enthalpic Barrier, ?H
Enthalpy of Reaction, ?Hrxn
Steps of the Bergman Reaction and Corresponding
Energies
17Benchmark 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
18MTC 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
19Effects 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
20cyclization
Enthalpic Barrier, ?H
Enthalpy of Reaction, ?Hrxn
Steps of the Bergman Reaction and Corresponding
Energies
21Energetic 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
22More 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
23Negative 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
24Cell Division
- In both Mitosis Meiosis DNA replication is a
crucial step - If DNA is changed, the new cells will be
ineffective or harmful
25Cell Mutation
- Mutations are permanent alterations in the
structure of DNA - Possible production of harmful cancer cells
26Cell 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
27Conclusions
- 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
28Future Considerations
- Make enediyne antibiotics which distinguish
between cancerous and healthy cells - Apply ONIOM hybrid theory to other members of
enediyne family
29Acknowledgements
- Dr. Parish
- Wazo Kristin
- Kid I kicked out of this room last night