The specific aim of this work is the synthesis and biomedical evaluation of water-soluble porphyrins and phthalocyanines containing polyhedral borane derivatives. The boranes to be attached include derivatives of icosahedral neutral carboranes, B10C2H12 and borane anions, B12H122-, and dodecahedral borane anions, B10H102-. Both natural and synthetic classes of porphyrins will serve as substrates for cage attachment, while in the phthalocyanines linkage will be effected through reactive side groups appended to the aromatic azaporphyrin rings. A variety of linkage chemistries are proposed which exploit the extensive derivative chemistries of boranes and nitrogen macrocycles. Water solubility in the carborane derivatives is to be achieved by several methods including cage opening, carboxylation and sulfonylation of the synthetic macrocycles and by beta-pyrrole propionic acid residues in the natural porphyrin series. The charged borane anion derivatives are expected to be inherently water-soluble. Biomedical evaluation of new compounds will include both in vitro and in vivo localization and toxicological studies carried out in collaboration with a group at Brookhaven National Laboratories. In suitable cases neutron capture therapy experimental trials in animal will follow. The long term objectives of the proposed work are: (1) to prepare boronated macrocycles which will selectively accumulate in tumor cells, and (2) to better understand the factors which influence tumor localization of porphyrins and phthalocyanines. The use of boron compounds in the treatment of human cancer is based on the unique property of non-radioactive 10B to absorb thermal neutrons. The prompt nuclear fissions which ensure deliver a dose of nearly 2.8 MeV only in the vicinity of boron-containing cells since the nuclear fragments produced (alpha particles and lithium atoms) travel only 10-15mm. Previous work in our laboratory has shown that: (1) water-soluble carboranyl porphyrins of several types can be successfully prepared, and (2) many of these accumulate in a model tumor system in therapeutic amounts. One of these is a unique porphyrin which produces sustained tumor boron levels at least twice those of any other reported compound including the one currently used clinically in Japan. In light of our very encouraging initial results in this area, funds are requested for a significant enhancement of our efforts.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Medicinal Chemistry Study Section (MCHA)
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University of California San Francisco
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