Roy P. Planalp Research

Current Research Interests

We are studying the chemistry of metal ions in relation to their roles and their potential therapeutic effects in living organisms. Metal ions are essential to functioning of all life forms. Our specific goals are to understand the chemistry of divalent or trivalent states of Mn, Fe, Co, Ni, Cu and Zn, and to design and study novel chelating agents. We are assessing effects of chelating agents on cellular metal metabolism and in connection with these effects, their potential as antitumor agents. In a second project, we study the chemistry of metal complexes' interactions with DNA, RNA, polypeptides and other biomolecules, including effects on cells and cytotoxicity. In all projects, we elucidate aqueous metal-binding properties, reactions at coordinated metals including redox, and structure of metal complexes.

Use of chelators to affect metal metabolism in organisms requires an understanding of selective aqueous metal complexation, solution speciation, redox and other parameters. Use of the novel "tach" chelator system has contributed insight because tach allows systematic variations of donor groups bound to nitrogen while retaining the tripodal framework (Figure 1); similar approaches with other chelator frameworks including "tren" are also underway. We have noted substantial in vitro tumor cell cytotoxicity of the tach family (e.g., IC50 for tachpyr treatment of mouse bladder tumor cells = 4.6 m M) and pursue the biological hypothesis that cellular metal ion depletion by chelators is a cause. In the tach system, we have identified chelators with thermodynamic metal-bindingselectivity for Fe(II) over Zn(II) or for Zn(II) over Fe(II). The basis for this selectivity has been elucidated and further tuning of binding properties by appropriate chelator derivatization is in progress; the binding properties have also been successfully correlated to biological activity. Additionally, iron is a specific mediator of redox reactions in tach and tren chelators, relative to Ni, Cu and Zn, an effect that may serve to enhance cytotoxicity and inertness of metal complexes via Fe(II)-(1,2-diimino) group formation. We continue to study relationships of metal chelation chemistry to biological effects and are investigating these chelators as potential antiproliferative agents.

 

We are also interested in metal complexes that are able to promote hydrolytic or oxidative degradation of DNA, RNA, proteins or other biopolymers. We have recently characterized the solution and solid-state structures of Cu(II)-triamine complexes, which promote the hydrolysis of phosphate diesters (Figure 2). A mechanistic study has uncovered a relatively unusual binuclear mechanism of ester cleavage and characterized possible active species. Further study is to focus on improving rates and stability of the catalysts. The DNA cleavage activity and analogy to natural metallonucleases is under study in collaboration with the N.I.H.

My program offers the student a broad training in synthetic inorganic, analytical and physical-inorganic chemistry. Coworkers may also be involved in our ongoing collaborations with groups in the biological and medical sciences. My former students are now placed in a variety of situations, typically in pharmaceutical and biotechnology companies. Students who wish to apply for graduate study may contact me directly (roy.planalp@unh.edu) or request information through the Chemistry Department.

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