Abstract

This project addresses fundamental issues regarding the synthesis and biological activity of naturally occurring tetrapyrroles. Phytochrome (Pr) is a linear tetrapyrrole that serves as the """"""""on-off"""""""" switch in photomorphogenesis. Its mode of action remains unclear. Employing recombinant DNA techniques, together with total synthesis, it is possible to prepare specifically 13c-labelled native Pr (*). Raman spectroscopy will be used to probe configuration and conformation changes during photoactivation of Pr. A number of synthetic phytochromobilin analogs will be reincorporated with the apoprotein C to probe the Pr binding pocket. New methodology will be applied to the synthesis and study of biologically active tetrapyrroles of the chlorin, bacteriochlorin and corrin class. Certain of these compounds show considerable promise in tumor photodynamic therapy, the process by which malignant tissue can be selectively destroyed by site-specific generation of singlet oxygen. In addition, bacteriochlorins of the tolyporphin class inhibit """"""""multi-drug resistance,"""""""" a common problem in cancer chemotherapy. Cobyric acid is the tetrapyrrole nucleus of vitamin B 12. Practical syntheses of these materials, and analogs, are currently not available.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038913-15
Application #
6635963
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1987-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
15
Fiscal Year
2003
Total Cost
$250,430
Indirect Cost

  Institution

Name
Dartmouth College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755

  Publications

Dror, Shimshon Ben; Bronshtein, Irena; Garini, Yuval et al. (2009) The localization and photosensitization of modified chlorin photosensitizers in artificial membranes. Photochem Photobiol Sci 8:354-61
Ben Dror, Shimshon; Bronshtein, Irena; Weitman, Hana et al. (2009) The binding of analogs of porphyrins and chlorins with elongated side chains to albumin. Eur Biophys J 38:847-55
Wang, Hui; Tassa, Carlos; Jacobi, Peter A (2008) Toward the synthesis of cobyric acid. Enantioselective syntheses of completely differentiated ring D synthons. Org Lett 10:2837-40
O'Neal, William G; Jacobi, Peter A (2008) Toward a general synthesis of chlorins. J Am Chem Soc 130:1102-8
O'Neal, William G; Roberts, William P; Ghosh, Indranath et al. (2006) Studies in chlorin chemistry. 3. A practical synthesis of c,d-ring symmetric chlorins of potential utility in photodynamic therapy. J Org Chem 71:3472-80
O'Neal, William G; Roberts, William P; Ghosh, Indranath et al. (2005) Studies in chlorin chemistry. II. A versatile synthesis of dihydrodipyrrins. J Org Chem 70:7243-51
Jacobi, Peter A; Adel Odeh, Imad M; Buddhu, Subhas C et al. (2005) Synthetic Studies in Phytochrome Chemistry. Synlett :2861-2885
Jacobi, Peter A; Li, Yongkai (2003) Enantioselective syntheses of ring-C precursors of vit. B(12). Reagent control. Org Lett 5:701-4
Jacobi, Peter A; Tassa, Carlos (2003) Enantioselective syntheses of ring-C precursors of vitamin B12. Substrate control. A novel Si-assisted elimination of vinyl bromides. Org Lett 5:4879-82
Ghosh, Indranath; Jacobi, Peter A (2002) Lewis acid-promoted oxidative addition of thioimidates to Pd0. J Org Chem 67:9304-9

Showing the most recent 10 out of 17 publications