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Author

Paul Schaffer

Date of Award

3-2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Supervisor

Professor John Fitzmaurice Valliant

Abstract

Dicarba-closo-dodecaboranes, otherwise known as carboranes, are attractive synthons for the development of inorganic pharmaceuticals and biological probes because of their unique chemical and physical properties. This thesis describes the synthesis and characterization of carborane derivatives as novel pharmaceuticals, radiopharmaceuticals and boron neutron capture therapy (BNCT) agents. Two general strategies were undertaken to prepare such compounds.

The first strategy, discussed in chapter 2, involved incorporating a carborane within the backbone of a known anti-cancer agent. To this end, a stereoselective synthetic methodology for incorporating a carborane into the structure of tamoxifen was developed. The reported synthetic approach yielded the desitred carborane derivative possessing a nido-carborance in place of on eof the aromatic rings of tamoxifen. The nido-carborane 2.28 showed modest affinity to the estrogen receptor (ER) which suggests that the inclusion of a carborane into the basic core of tamoxifen is a viable strategy for developing new antiestrogens and BNCT agents.

Having established the synthetic methodology for the nido-carborane analogue of tamoxifen 2.28, subsequent research efforts focused on attatching a metal center to the open face of the carborane cage. The [Re(CO)3]+ core was attached to the open face of 2.28 as a test toward the feasibility of this approach. While the reaction did yield some of the target complex 2.31, the yield was low and accompanied by the formation of a significant quantity of Re(CO)3 clusters, leaving mostly unreacted starting material as the major reaction component. The detection of 2.31 demonstrates that the 99mTc analogue can be prepared and potentially used as a novel imaging agent.

In parallel to the work involving tamoxifen, chapters 4 and 5 discuss novel synthetic methodologies developed to facilitate the synthesis of metal-based BNCT agents. Two homoleptic Re(I) [Re(L6)]+ (L = ortho or para-carborane isonitrile) complexes of ortho and para-carborane isocyanide ligands were prepared. These compounds are designed to serve as a new class of BNCT agent whose distribution can be evaluated using standard radioimaging techniques. These complexes are attractive agents for neutron capture therapy because of their exceptionally high boron content, the ease with which they can be targeted to specific receptors, and the fact that the biodistribution can be determined non-invasively using radioimaging techniques.

The synthesis and coordination chemistry of both the ortho- and para-carborane isocyanide complexes were examined through the reaction of [Re2(O2CPh)4Cl2] and [Re2(OAc)4Cl2] with 3-isocyano-1,2-dicarba-closo-dodecaborane and a unique para-carborane azetidine derivative respectively. This research revealed some unexpected differences between the chemistry of ortho- and para-carboranes.

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