Living Cell as a Self-Synchronized Chemical Reactor.

Thermal fluctuations power all processes inside living cells. Therefore, these processes are inherently random. However, myriad multistep chemical reactions act in concerto inside a cell, finally leading to this chemical reactor's self-replication. We speculate that an underlying mechanism in nature must exist that allows all of these reactions to synchronize at multiple time and length scales, overcoming in this way the random nature of any single process in a cell. This Perspective discusses what type of research is needed to understand this undiscovered synchronization law.

Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications.

Targeting cap-dependent translation initiation is one of the experimental approaches that could lead to the development of novel anti-cancer therapies. Synthetic dinucleoside 5',5'-triphosphates cap analogs are potent antagonists of eukaryotic translation initiation factor 4E (eIF4E) in vitro and could counteract elevated levels of eIF4E in cancer cells; however, transformation of these compounds into therapeutic agents remains challenging - they do not easily penetrate into cells and are susceptible to enzymatic cleavage. Here, we tested the potential of several small molecule ligands - folic acid, biotin, glucose, and cholesterol - to deliver both hydrolyzable and cleavage-resistant cap analogs into cells. A broad structure-activity relationship (SAR) study using model fluorescent probes and cap-ligand conjugates showed that cholesterol greatly facilitates uptake of cap analogs without disturbing the interactions with eIF4E. The most potent cholesterol conjugate identified showed apoptosis-mediated cytotoxicity towards cancer cells.