Identification of Adenosine Deaminase Inhibitors by Metal-binding Pharmacophore Screening.

Adenosine deaminase (ADA) is a human mononuclear Zn2+ metalloenzyme that converts adenosine to inosine. ADA is a validated drug target for cancer, but there has been little recent work on the development of new therapeutics against this enzyme. The lack of new advancements can be partially attributed to an absence of suitable assays for high-throughput screening (HTS) against ADA. To facilitate more rapid drug discovery efforts for this target, an in vitro assay was developed that utilizes the enzymatic conversion of a visibly emitting adenosine analogue to the corresponding fluorescent inosine analogue by ADA, which can be monitored via fluorescence intensity changes. Utilizing this assay, a library of ∼350 small molecules containing metal-binding pharmacophores (MBPs) was screened in an HTS format to identify new inhibitor scaffolds against ADA. This approach yielded a new metal-binding scaffold with a Ki value of 26±1 µM.

Isoreticular synthesis and modification of frameworks with the UiO-66 topology.

Amino, bromo, nitro, and naphthalene functionalized UiO-66 metal-organic frameworks have been synthesized through reticular chemistry. UiO-66-NH(2) is shown to be suitable for postsynthetic modification with a variety of anhydrides to generate new, functionalized frameworks.

A macrophage cell model for selective metalloproteinase inhibitor design.

The desire to inhibit zinc-dependent matrix metalloproteinases (MMPs) has, over the course of the last 30 years, led to the development of a plethora of MMP inhibitors that bind directly to the active-site metal. With one exception, all of these drugs have failed in clinical trials, due to many factors, including an apparent lack of specificity for MMPs. To address the question of whether these inhibitors are selective for MMPs in a biological setting, a cell-based screening method is presented to compare the relative activities of zinc, heme iron, and non-heme iron enzymes in the presence of these compounds using the RAW264.7 macrophage cell line. We screened nine different zinc-binding groups (ZBGs), four established MMP inhibitors (MMPis), and two novel MMP inhibitors developed in our laboratory to determine their selectivities against five different metalloenzymes. Using this model, we identified two nitrogen donor compounds--2,2'-dipyridylamine (DPA) and triazacyclononane (TACN)--as the most selective ZBGs for zinc metalloenzyme inhibitor development. We also demonstrated that the model could predict known nonspecific interactions of some of the most commonly used MMPis, and could also give cross-reactivity information for newly developed MMPis. This work demonstrates the utility of cell-based assays in both the design and the screening of novel metalloenzyme inhibitors.

Self-assembly of heteroleptic [Cu(dipyrrinato)(hfacac)] complexes directed by fluorine-fluorine interactions.

Heteroleptic copper(II) complexes were synthesized from three different meso-substituted pyridyl- and quinoline-dipyrrinato ligands (3-pyrdpm, 3-quindpm, and 4-quindpm). Metal complexes were prepared with both acetylacetonate (acac) and hexafluoroacetylactonate (hfacac) ancillary ligands. The complexes undergo a self-complementary self-assembly process upon crystallization to generate a range of solid-state topologies including one-dimensional coordination polymers and discrete hexameric rings. The self-assembly of these molecular aggregates is driven by metal-ligand bonding, but is also modulated by fluorine-fluorine interactions. Perfluorination of the spectator ligand tends to generate more compact structures, which is attributed to aggregation of the perfluoromethyl groups. The results presented here demonstrate that fluorine-fluorine contacts can be used to modulate supramolecular structures in the solid state.

Adjuvant therapy for rectal cancer in the elderly.

Rectal cancer, like most malignancies, is a disease of older age. By the year 2030, nearly 70% of all cancer patients are expected to be over the age of 65 years. Adjuvant therapy for colorectal cancer has been one of the most important contributions of medical oncology to the health of the population, saving more lives annually than more effective therapy for less common cancers, such as Hodgkin's disease. Nonetheless, population-based studies have shown that less than half of those over the age of 65 years receive the standard adjuvant therapy for rectal cancer. In many instances, there may be legitimate reasons for this, but efforts must be made to overcome any age bias and nihilism in the use of adjuvant therapy in the treatment of rectal cancer in the elderly. Although the elderly have been under-represented in clinical trials, they have been shown to tolerate cancer treatment and derive benefit from the adjuvant therapies. Despite early reports to the contrary, older patients have been shown to tolerate surgical resections for rectal cancer as well as their younger counterparts. Studies have supported the use of combined modality therapy as standard adjuvant care for clinical T3 rectal cancer in the preoperative setting and for patients with T3 and/or N1/N2 disease in the postoperative setting, wtih improved rates of sphincter preservation, recurrence and overall survival.