Influence of stereochemistry on the activity of rapadocin, an isoform-specific inhibitor of the nucleoside transporter ENT1.

Rapadocin is a novel rapamycin-inspired polyketide-tetrapeptide hybrid macrocycle that possesses highly potent and isoform-specific inhibitory activity against the human equilibrative nucleoside transporter 1 (hENT1). Rapadocin contains an epimerizable chiral center in phenylglycine and an olefin group, and can thus exist as a mixture of four stereoisomers. Herein, we report the first total synthesis of the four stereoisomers of rapadocin using two different synthetic strategies and the assignment of their structures.

Rapamycin-inspired macrocycles with new target specificity.

Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles (named rapafucins) using optimized FKBP-binding domains.

Effects of a Tablet Computer on Self-care, Quality of Life, and Knowledge: A Randomized Clinical Trial.

Background: Conflicting results have been reported for telemonitoring in patients with heart failure (HF). We wanted to evaluate whether patients using a tablet computer aimed at improving self-care behavior could do so and also whether it affects quality of life and health-related quality of life, disease knowledge, and in-hospital days.

Methods And Results: Patients with HF (n = 82) were randomized to the intervention group (IG) with a tablet computer (giving information and advice) or the control group (CG) that was subject to standard care.

Parasite Polyamines as Pharmaceutical Targets.

There is an urgent need for the identification and validation of new therapeutic targets in protozoan parasites because currently available drugs are limited in number and usefulness, and no vaccines are available. The discovery that alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, is an efficacious treatment for African Sleeping Sickness caused by the protozoan parasite Trypanosoma brucei, has validated the polyamine pathway as a target in protozoan parasites. Polyamines are ubiquitous organic cations that play critical roles in key cellular processes such as growth, differentiation, and macromolecular biosynthesis.