We have shown that Mn(II) complexes of pentaaza-15-membered macrocyclic ligands (Mn(PAM)) can be very active catalysts for the dismutation of superoxide radical to oxygen and hydrogen peroxide. The design of active agents utilizing Molecular Mechanics (MM) is described as well as the key structural factors governing activity and stability. Increasing the number of substituents on the carbon sites of the macrocycle adds rigidity to the macrocyclic ligand bound to the Mn(II) center and thus increases the kinetic stability of the complex. The position of substituents and their stereochemistry dictate the catalytic activity. The complex <b>GC4419</b> will be described and the key factors that dictated its choice as an agent to take into clinical trials for patients receiving radiation therapy for treatment of head and neck cancer in which the treatment side effects (oral mucositis (OM)) are very severe and debilitating. The efficacy of GC4419 in reducing the duration and incidence of severe OM in human subjects at safe doses has been demonstrated in human clinical studies with very positive results such that the FDA has recently granted it Breakthrough Therapy Designation for addressing this unmet medical need. The issues involved in the synthesis of this class (Mn(PAM)) of drug weigh heavily on the choice of compound to develop as do more traditional aspects of medicinal chemistry such as toxicity and efficacy which will also be addressed.

Design and development of a synthetic enzyme for use as a pharmaceutical agent to reduce the undesired side effects of radiation treatment in cancer therapy

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.