CWRU 02/05/2004

Non-Invasive Cancer TherapyNon-Invasive Cancer Therapy

Vladimir V. Popik, Ph.D.Vladimir V. Popik, Ph.D.

Idea Award RecipientIdea Award Recipient

CWRU 02/05/2004

Scope of ResearchScope of Research

The majority of conventional anti-tumor drugs work either by damaging the DNA molecules (e.g., cis-platinum, bleomycin, and dynemicin A) or by interfering with the cell replication process (e.g., taxol and colhicine). This prevents cell division

and eventually leads to the cell death. Lack of selectivity is a major problem of modern anticancer

chemotherapy We propose to develop anti-cancer antibiotics that have no

cytotoxicity in the dark but are selectively activated in the target tissue by irradiation with the red laser.

Since the simultaneous presence of both photoactivatable antibiotics and light are required to develop toxicity, damage to healthy [breast] tissues can be minimized.

CWRU 02/05/2004

StrategyStrategy

Incorporate a photo-triggering device in place of the chemical trigger of natural anti-tumor antibiotics; in other words, develop anti-cancer “laser guided missiles.”

Modification of only the central fragment of enediyne antibiotics allows the preservation and use of those structural features that are responsible for the bioavailability and activity of these natural products.

CWRU 02/05/2004

OOOOHH3COCH3OOOOOHOOHNHCH3

Natural Antitumor Enediyne AntibioticsNatural Antitumor Enediyne Antibiotics

Calicheamicin 1

Dynemicin A

Esperamicin

Neocarzinostatin

Bergman Cyclization

CWRU 02/05/2004

Photochemical Activation of Bergman Photochemical Activation of Bergman

CyclizationCyclization

CONCEPT # 1Ring Contraction

XN2OXCO2HOXOX-N2hνXCOXH2OOOOOX = CH2, O, NH

Ring contraction using photo-Wolff reaction

Stable ½ = 18 h at 360C

Xhνl

CWRU 02/05/2004

XYhνXYhν

In-situ In-situ Generation of Enediyne Generation of Enediyne -System-System

CONCEPT # 2Triple Bond Generation

CONCEPT # 3Double Bond Generation

10-memberedring enediyne

9-memberedring enediyne

XYhνXYhν

CWRU 02/05/2004

In-situ In-situ Generation of Enediyne Generation of Enediyne -System-System

YOhν- COOXRRYOXRRYRROXY= O, NR, CH2

ON2OOXOX-N2hνH2OOOOHHOXOCO

CWRU 02/05/2004

Frontier Molecular Orbitals of Diazo Meldrum’s AcidFrontier Molecular Orbitals of Diazo Meldrum’s Acid

HOMO LUMO

0

0.2

0.4

0.6

0.8

1

200 250 300 350 400

Wavelength / nm

Absorbance

X 400

X 20

TD B3PW91/ 6-311+G(3df,2p) :

S1 HOMO LUMO

HOMO-1

S2 HOMO-1 LUMO

CWRU 02/05/2004

Photochemistry of Diazo Meldrum’s AcidPhotochemistry of Diazo Meldrum’s AcidOOOON2OOOONNS0S1S2

254 nmInt.Conv.OOOCO

355 nm~ 3%~ 34%

~ 66%~ 95%T1OOOO 254 nm, sens.1-3%ISC

CWRU 02/05/2004

Conformational Equilibrium of Diethyl DiazomalonateConformational Equilibrium of Diethyl Diazomalonate(Energies from MP2(full)/aug-cc-pVTZ//B3LYP/6-311G+(3df,2p))(Energies from MP2(full)/aug-cc-pVTZ//B3LYP/6-311G+(3df,2p))

OOOON2OOOON2OOOON2 Z,ZZ,EE,E

EREL (kcal/mol) 0.02 0.00 0.82

E# 8.32 9.81

G≠213=9.3 kcal/mol G≠

203=9.3 kcal/mol

CWRU 02/05/2004

X-Ray Structures of Na and K complexes of DiazoCrownetherX-Ray Structures of Na and K complexes of DiazoCrownether

Na+

K+

Z,E

Z,Z

CWRU 02/05/2004

PES of Diazo Meldrum’s Acid DeazotizationPES of Diazo Meldrum’s Acid Deazotization

OOOO

OOOON2

OOOCO

b3lyp/6-31+G**

CWRU 02/05/2004

Geometry Changes Accompanying Loss of Nitrogen from Geometry Changes Accompanying Loss of Nitrogen from Diazo Meldrum’s Acid Diazo Meldrum’s Acid

1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8

C - N distance (A)

CWRU 02/05/2004

PES for Nitrogen Extrusion From Z,Z PES for Nitrogen Extrusion From Z,Z DiazomalonateDiazomalonate

OON2OO

OOOO

OOOCOb3lyp/6-31+G**

CWRU 02/05/2004

1.41.6

1.82.0

2.22.4

2.6

0

50

100

2.4

2.2

2.0

1.8

1.6

EREL

(kcal/Mol)

C1 - C

3 distance (A)

C1 - N

8 distance (A)

PES for Nitrogen Extrusion From PES for Nitrogen Extrusion From DiazocyclohexanoneDiazocyclohexanone

ON2

CO

O

b3lyp/6-31+G**

CWRU 02/05/2004

Decomposition of Diazocyclohexanone Decomposition of Diazocyclohexanone

CWRU 02/05/2004

1.41.6

1.82.0

2.22.4

2.6

-20

0

20

40

60

80

100

120

140

160

180

2.4

2.2

2.0

1.8

1.6

EREL

(kcal/Mol)

C - C distance (A)

C - N distance (A)

PES for Nitrogen Extrusion From Z-DiazobutanonePES for Nitrogen Extrusion From Z-Diazobutanone

ON2

O

CO

b3lyp/6-31+G**

CWRU 02/05/2004

Synthesis of 2-Diazo-1,3-dioxocycloundeca-6-en-4,7-diyneSynthesis of 2-Diazo-1,3-dioxocycloundeca-6-en-4,7-diyne

N2OO

CWRU 02/05/2004

Ring contraction using photo-Wolff reactionRing contraction using photo-Wolff reaction

N2OCO2i-PrhνOOOO+i-PrOH

30% 50%

CWRU 02/05/2004

MethodologyMethodology

Administer photoactivatable enediynes to breast cancer patients Irradiate cancerous tissues through the skin with pulses of

ultrafast near infrared laser (such as Ti:Sapphire) Extremely cytotoxic enediyne are generated only in irradiated

tissues, eventually destroying the tumor