The enediyne antitumor antibiotics possess the unusual (Z)- 1 ,5-diyne-3-ene unit that rearranges in the presence of biological reducing equivalents to form a 1 ,4-phenyl diradical intermediate that performs double H-atom abstraction from cellular DNA. Upon discovery of these intriguing structures in the late 1980s, the pharmaceutical industry became interested in the potential use of enediynes as therapeutic antitumor agents. Unfortunately, after intense investigation by Eli Lilly, Wyeth-Ayerst, and Bristol Myers-Squibb, the compounds were determined to be too cytotoxic due to the inability to control their thermal reactivities effectively. Recent biomimetic enediyne studies have revealed that 1) the physical distance between the alkyne termini, and 2) the electronic structure and redox state of the enediyne chromophore adjacent to the reactive subunit are important factors that influence thermal enediyne reactivity. Additionally, the demonstration that the enediyne natural products can also be cyclized photochemically fostered questions regarding 3) the mechanism of photoactivated enediyne cyclization. Although the biologically relevant enediynes known to date are all organic compounds, transition metals routinely exert geometric and electronic influences on bound organic ligands. That is, they intricately poise ligand geometries, modulate electronic structures of bound ligands, and initiate thermal and photochemical redox reactions with bound organic substrates. For these reasons, metal ions are outstanding probes of enediyne reactivity. We have focused our research efforts on using metal ions to develop an understanding of the factors that control thermal and photochemical enediyne cyclization, and to incorporate this information into the design of synthetically accessible """"""""metalloenediynes"""""""" that exhibit controlled thermal and photochemical reactivities for potential biological applications. This proposal outlines studies designed to probe fundamental chemical questions regarding enediyne reactivity as well as initiating biological activity studies in cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM062541-01A1
Application #
6400134
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Preusch, Peter C
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$207,803
Indirect Cost
Name
Indiana University Bloomington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Bhattacharyya, Sibaprasad; Clark, Aurora E; Pink, Maren et al. (2009) Structure modulated electronic contributions to metalloenediyne reactivity: synthesis and thermal Bergman cyclization of MLX2 compounds. Inorg Chem 48:3916-25
Nath, Mahendra; Pink, Maren; Zaleski, Jeffrey M (2005) Controlling both ground- and excited-state thermal barriers to Bergman cyclization with alkyne termini substitution. J Am Chem Soc 127:478-9
Bhattacharyya, Sibaprasad; Pink, Maren; Baik, Mu-Hyun et al. (2005) A unique approach to metal-induced Bergman cyclization: long-range enediyne activation by ligand-to-metal charge transfer. Angew Chem Int Ed Engl 44:592-5
Bhattacharyya, Sibaprasad; Dye, David F; Pink, Maren et al. (2005) A geometric switching approach toward thermal activation of metalloenediynes. Chem Commun (Camb) :5295-7
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Kraft, Brian J; Coalter, Nicole L; Nath, Mahendra et al. (2003) Photothermally induced Bergman cyclization of metalloenediynes via near-infrared ligand-to-metal charge-transfer excitation. Inorg Chem 42:1663-72
Nath, Mahendra; Huffman, John C; Zaleski, Jeffrey M (2003) Ambient temperature activation of haloporphyrinic-enediynes: electronic contributions to bergman cycloaromatization. J Am Chem Soc 125:11484-5
Benites, Pedro J; Holmberg, Rebecca C; Rawat, Diwan S et al. (2003) Metal-ligand charge-transfer-promoted photoelectronic Bergman cyclization of copper metalloenediynes: photochemical DNA cleavage via C-4' H-atom abstraction. J Am Chem Soc 125:6434-46
Clark, Aurora E; Davidson, Ernest R; Zaleski, Jeffrey M (2003) A TDDFT description of the low-energy excited states of copper and zinc metalloenediynes. Chem Commun (Camb) :2876-7
Chandra, Tilak; Kraft, Brian J; Huffman, John C et al. (2003) Synthesis and structural characterization of porphyrinic enediynes: geometric and electronic effects on thermal and photochemical reactivity. Inorg Chem 42:5158-72

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