Essays on Procurement, Scoring Auction, and Quality Manipulation Corruption

Thesis (Ph.D.)--University of Washington, 2016-06

Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity

There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.

PCTH: A novel orally active chelator for the treatment of iron overload disease

Our laboratories have prepared a novel class of iron (Fe) chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. This article will review the iron chelation efficacy of this series of chelators, both in cell culture and in animal models. Several PCIH analogs were shown to be effective at inducing iron mobilization and preventing iron uptake from the iron-transport protein, transferrin. Moreover, several of these ligands were effective at permeating the mitochondrion and inducing iron release. Studies in mice demonstrated that the PCIH analog, PCTH, was orally active and well tolerated by mice at doses ranging from 50 to 100 mg kg(-1) , twice daily (b.d.). A dose-dependent increase in fecal Fe-59 excretion was observed in the PCTH-treated group. This level of iron excretion was similar to that found for the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). The PCIH group of ligands clearly has the potential for the treatment of ss-thalassemia (thal) and Friedreich's Ataxia (FA).

Kitchen, Lahz House, Spring Hill

Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Lahz House, Spring Hill

Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Lahz House, Spring Hill

As seen from opposite side of street. Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Kitchen and dining area, Lahz House, Spring Hill

View to new kitchen and dining area, as seen from sitting room. Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Lahz House, Spring Hill

As seen from opposite side of street. Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Verandah, Lahz House, Spring Hill

Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Verandah, Lahz House, Spring Hill

Winner of the Robin Dods Award RAIA Queensland Chapter 1990

Verandah, Lahz House, Spring Hill

Winner of the Robin Dods Award RAIA Queensland Chapter 1990