Biomedical subjects

John A Tallarico

Publications and source records attributed to John A Tallarico.

6 recordsLinked to original sources

PubMed2005

Small-molecule diversity using a skeletal transformation strategy.

[reaction: see text] We describe a short synthetic sequence resulting in >4000 skeletally diverse small molecules that have three distinct skeletal frameworks among other unique structural features. The sequence entails skeletal transformations pioneered by Winterfeldt and co-workers. We use epoxide ring openings and subsequent functionalizations that provide, e.g., spirocyclic oxazolidines, Lewis acid catalyzed Diels-Alder reactions of a steroid-derived diene that afford stable and isolable ring B adducts, and subsequent retro-Diels-Alder fragmentations that yield 14-membered paracyclophanes.

Catalysis↗

PubMed2005

A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes.

The spindle checkpoint prevents chromosome loss by preventing chromosome segregation in cells with improperly attached chromosomes [1, 2 and 3]. The checkpoint senses defects in the attachment of chromosomes to the mitotic spindle [4] and the tension exerted on chromosomes by spindle forces in mitosis [5, 6 and 7]. Because many cancers have defects in chromosome segregation, this checkpoint may be required for survival of tumor cells and may be a target for chemotherapy. We performed a phenotype-based chemical-genetic screen in budding yeast and identified an inhibitor of the spindle checkpoint, called cincreasin. We used a genome-wide collection of yeast gene-deletion strains and traditional genetic and biochemical analysis to show that the target of cincreasin is Mps1, a protein kinase required for checkpoint function [8]. Despite the requirement for Mps1 for sensing both the lack of microtubule attachment and tension at kinetochores, we find concentrations of cincreasin that selectively inhibit the tension-sensitive branch of the spindle checkpoint. At these concentrations, cincreasin causes lethal chromosome missegregation in mutants that display chromosomal instability. Our results demonstrate that Mps1 can be exploited as a target and that inhibiting the tension-sensitive branch of the spindle checkpoint may be a way of selectively killing cancer cells that display chromosomal instability.

Bromobenzenes↗

PubMed2005

Small molecules that delay S phase suppress a zebrafish bmyb mutant.

Bmyb is a ubiquitously expressed transcription factor involved in cellular proliferation and cancer. Loss of bmyb function in the zebrafish mutant crash&burn (crb) results in decreased cyclin B1 expression, mitotic arrest and genome instability. These phenotypic observations in crb mutants could be attributed to the decreased expression of cyclin B1, a cell-cycle regulatory protein that is responsible for driving cell progression from G2 through mitosis. To identify small molecules that interact with the bmyb pathway, we developed an embryo-based suppressor screening strategy. In 16 weeks we screened a diverse approximately 16,000 compound library, and discovered one previously unknown compound, persynthamide (psy, 1), that suppressed bmyb-dependent mitotic defects. Psy-treated embryos showed an S-phase delay, and knockdown of the cell-cycle checkpoint regulator ataxia telangiectasia--and Rad-related kinase (ATR) abrogated the suppression of crb. The DNA synthesis inhibitors aphidicolin (2) and hydroxyurea (3) also suppressed crb. S-phase inhibition upregulated cyclin B1 mRNA, promoting the progression of cells through mitosis. Our study demonstrates that chemical suppressor screening in zebrafish can identify compounds with cell-cycle activity and can be used to identify pathways that interact with specific cell-cycle phenotypes.

Adamantane↗

PubMed2004

Demonstration of the feasibility of a direct solid-phase split-pool Biginelli synthesis of 3,4-dihydropyrimidinones.

[reaction: see text] A direct, Lewis acid-catalyzed Biginelli synthesis of 3,4-dihydropyrimidinones has been performed on high-capacity polystyrene macrobeads with a polymer O-silyl-attached N-(3-hydroxypropyl)urea. Resin-urea was first reacted separately with either 4-bromo- or 4-chlorobenzaldehyde and LiOTf in MeCN at 80 degrees C. After washing, the beads were pooled and reacted with ethyl acetoacetate and LiOTf in MeCN at 80 degrees C. Formation of only one kind of Biginelli product per bead demonstrated the feasibility of a solid-phase non-Atwal two-step split-and-pool synthesis of 3,4-dihydropyrimidinones.

Catalysis↗

PubMed2004

The modular approach to ligand discovery.

Identifying specific protein-ligand interactions is a long-standing problem in drug discovery and chemical biology, which is only exacerbated by the abundance of uncharacterized proteins revealed by genomics. Last month in Chemistry Biology, Sem et al. described a powerful technique for rapidly screening protein families for ligands.

Drug Evaluation, Preclinical↗

PubMed2002

Intramolecular cycloadditions of cyclobutadiene with olefins.

Intramolecular cycloadditions between cyclobutadiene and olefins can provide highly functionalized cyclobutene-containing products. The outcome of the reaction depends on the nature of the tether connecting the two reactive partners in the cycloaddition. Electronically unactivated olefins attached to cyclobutadiene through a three-atom, heteroatom-containing tether yield successfully the desired cycloadducts, whereas the corresponding substrates without a heteroatom linkage or with a longer tether are less prone to undergo the intramolecular cycloaddition. Calculations were used to help uncover some of the factors that influence the course of the cycloaddition. Successful intramolecular reactions usually require either electronic activation of the dienophile, conformational restriction of the tether, or a slower oxidation protocol. In general, a facile intermolecular dimerization of cyclobutadiene is the major process that competes with the intramolecular cycloaddition.

Alkenes↗