1. CWRU 02/05/2004 Non-Invasive Cancer Therapy Vladimir V. Popik, Ph.D. Idea Award Recipient

2. CWRU 02/05/2004 Scope of Research l 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. l Lack of selectivity is a major problem of modern anticancer chemotherapy l 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. l Since the simultaneous presence of both photoactivatable antibiotics and light are required to develop toxicity, damage to healthy [breast] tissues can be minimized.

3. CWRU 02/05/2004 Strategy l 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.” l 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.

4. CWRU 02/05/2004 Natural Antitumor Enediyne Antibiotics Calicheamicin  1 Dynemicin A Esperamicin Neocarzinostatin Bergman Cyclization

5. CWRU 02/05/2004 Photochemical Activation of Bergman Cyclization CONCEPT # 1 Ring Contraction Ring contraction using photo-Wolff reaction Stable  ½ = 18 h at 36 0 C

6. CWRU 02/05/2004 In-situ Generation of Enediyne  -System CONCEPT # 2 Triple Bond Generation CONCEPT # 3 Double Bond Generation 10-membered ring enediyne 9-membered ring enediyne

7. CWRU 02/05/2004 In-situ Generation of Enediyne  -System

8. CWRU 02/05/2004 Frontier Molecular Orbitals of Diazo Meldrum’s Acid HOMO LUMO TD B3PW91/ 6-311+G(3df,2p) : S 1 HOMO LUMO HOMO-1 S 2 HOMO-1 LUMO

9. CWRU 02/05/2004 Photochemistry of Diazo Meldrum’s Acid

10. CWRU 02/05/2004 Conformational Equilibrium of Diethyl Diazomalonate (Energies from MP2(full)/aug-cc-pVTZ//B3LYP/6-311G+(3df,2p))  E REL (kcal/mol) 0.020.00 0.82  E # 8.32 9.81  G ≠ 213 =9.3 kcal/mol  G ≠ 203 =9.3 kcal/mol

11. CWRU 02/05/2004 X-Ray Structures of Na and K complexes of DiazoCrownether Na + K+K+ Z,E Z,Z

12. CWRU 02/05/2004 PES of Diazo Meldrum’s Acid Deazotization b3lyp/6-31+G**

13. CWRU 02/05/2004 Geometry Changes Accompanying Loss of Nitrogen from Diazo Meldrum’s Acid

14. CWRU 02/05/2004 PES for Nitrogen Extrusion From Z,Z Diazomalonate b3lyp/6-31+G**

15. CWRU 02/05/2004 PES for Nitrogen Extrusion From Diazocyclohexanone b3lyp/6-31+G**

16. CWRU 02/05/2004 Decomposition of Diazocyclohexanone

17. CWRU 02/05/2004 PES for Nitrogen Extrusion From Z-Diazobutanone b3lyp/6-31+G**

18. CWRU 02/05/2004 Synthesis of 2-Diazo-1,3-dioxocycloundeca-6-en-4,7-diyne

19. CWRU 02/05/2004 Ring contraction using photo-Wolff reaction 30% 50%

20. CWRU 02/05/2004 Methodology l Administer photoactivatable enediynes to breast cancer patients l Irradiate cancerous tissues through the skin with pulses of ultrafast near infrared laser (such as Ti:Sapphire) l Extremely cytotoxic enediyne are generated only in irradiated tissues, eventually destroying the tumor