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Postdoc project - Lars Jørgensen

Total Synthesis of Ingenol Mebutate

 

Natural products have been used in the treatment of various diseases since ancient times. Still today they play a significant role in the development of new pharmaceutical drugs. For instance, 47% of the small molecules, used in the treatment of cancer, put on the market since the 1940’s, have been natural products or derived from natural products.

 

Ingenol (1), a highly oxygenated tetracyclic diterpene, was isolated from the genus Euphorbia and characterized by Hecker in 1968. Various esters of ingenol (1) display remarkable biological properties, ranging from the activation of protein kinase C (PKC) and tumor-promoting properties of some derivatives to the anti-HIV, anti-tumor, or anti-leukemic properties of others.

In addition to the interesting pharmacology of these substances, the establishment of the highly unusual trans intrabridgehead stereochemistry of the BC ring system presents a particularly daunting challenge for synthetic organic chemists. Since the early 1980s, this combination of remarkable biological activities and complex structural architecture has received multidisciplinary attention, and ingenol (1) has been one of the most challenging targets for organic chemists over the past 30 years.

Ingenol mebutate (2), an ester of ingenol (1) isolated from Euphorbia peplus, is applied in the topical treatment of actinic (solar) keratosis (AK). AK, also known as sun spots, is a common pre-cancerous skin condition caused by sun exposure, which can develop into skin cancer if left untreated.

 

To date, three total syntheses and one formal synthesis of ingenol (1) have been published. These landmark works by Wood, Kuwajima, Kigoshi, and Winkler represented significant advances in the field of synthesis and allowed the first synthetic access to ingenol (1) and analogs. However, these syntheses are ranging from 36 steps to 45 steps, thus the overall yields are correspondingly low (0.002% - 0.01%). Hence these syntheses are not applicable to production of larger amounts of ingenol and derivatives. The development of a short and more efficient synthetic route to ingenol mebutate (2) would provide significant quantities of the natural product itself as well as analogs otherwise unavailable.

 

The specific aims of this research project are:

1. Short, scalable total synthesis of ingenol mebutate (2).

2. Development of methodologies applicable to the total synthesis of related natural products.

 

The highly strained trans-fused bicyclo[4.4.1]undecane ring system of this class of natural products, is the major challenge in the total synthesis of ingenol mebutate (2). Several approaches for constructing trans- as well as cis-fused ingenane skeletons have been developed, but only a few have succeeded in the former. The development of new methodologies for the synthesis of these structures is one of the main goals of this projekt. The methodologies developed will pave the way for a more efficient construction of these natural products.

 

This project is conducted at The Scripps Research Institute (TSRI), La Jolla, CA, USA. TSRI is renowned for its high level of organic synthesis.

1. Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over the last 25 years. Journal of Natural Products 2007, 70, 461-477.

2. Hecker, E. Cocarcinogenic Prinicples from Seed Oil of Croton Tiglium and from Other Euphorbiaceae. Cancer Research 1968, 28, 2338-2349.

3. Hasler, C. M.; Acs, G.; Blumberg, P. M. Specific Binding to Protein-Kinase-C by Ingenol and Its Induction of Biological Responses. Cancer Research 1992, 52, 202-208.

4. Sorg, B.; Schmidt, R.; Hecker, E. Structure-Activity-Relationships of Polyfunctional Diterpenes of the Ingenane Type .1. Tumor-Promoting Activity of Homologous, Aliphatic 3-Esters of Ingenol and of Delta-7,8-Isoingenol-3-Tetradecanoate. Carcinogenesis 1987, 8, 1-4.

5. Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Wang, G. Y. S.; Uemura, D.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M. Ingenol derivatives are highly potent and selective inhibitors of HIV replication in vitro. Antiviral Chemistry & Chemotherapy 1996, 7, 230-236.

6. Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K.; Wang, G. Y. S.; Uemura, D.; Yokota, T.; Baba, M. Mechanism of selective inhibition of human immunodeficiency virus by ingenol triacetate. Antimicrobial Agents and Chemotherapy 1996, 40, 271-273.

7. Fatope, M. O.; Zeng, L.; Ohayaga, J. E.; Shi, G.; McLaughlin, J. L. Selectively cytotoxic diterpenes from Euphorbia poisonii. Journal of Medicinal Chemistry 1996, 39, 1005-1008.

8. Alder, R. W.; East, S. P. In/out isomerism. Chemical Reviews 1996, 96, 2097-2111.

9. Kuwajima, I.; Tanino, K. Total synthesis of ingenol. Chemical Reviews 2005, 105, 4661-4670.

10. Anderson, L.; Schmieder, G. J.; Werschler, W. P.; Tschen, E. H.; Ling, M. R.; Stough, D. B.; Katsamas, J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. Journal of the American Academy of Dermatology 2009, 60, 934-943.

11. Siller, G.; Gebauer, K.; Welburn, P.; Katsamas, J.; Ogbourne, S. M. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: Results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australasian Journal of Dermatology 2009, 50, 16-22.

12. Siller, G.; Rosen, R.; Freeman, M.; Welburn, P.; Katsamas, J.; Ogbourne, S. M. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: Results of a randomized phase IIa trial. Australasian Journal of Dermatology 2010, 51, 99-105.

13. Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. Total synthesis of ingenol. Journal of the American Chemical Society 2004, 126, 16300-16301.

14. Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. Total synthesis of ingenol. Journal of the American Chemical Society 2003, 125, 1498-1500.

15. Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. Formal synthesis of optically active ingenol via ring-closing olefin metathesis. Journal of Organic Chemistry 2004, 69, 7802-7808.

16. Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. The first total synthesis of (+/-)-ingenol. Journal of the American Chemical Society 2002, 124, 9726-9728.

17. Kim, S.; Winkler, J. D. Approaches to the synthesis of ingenol. Chemical Society Reviews 1997, 26, 387-399.

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