A photoactivatable small molecule probe for the in vivo capture of polyketide intermediates

A photolabile carba(dethia) malonyl N‐acetylcysteamine derivative was devised and prepared for the trapping of biosynthetic polyketide intermediates following light activation. From the lasalocid A polyketide assembly in a mutant strain of the soil bacterium S. lasaliensis, a previously undetected cyclised intermediate was identified and characterised, providing a new outlook on the timing of substrate processing

Infrared spectroscopy of small-molecule endofullerenes

Hydrogen is one of the few molecules which has been incarcerated in the molecular cage of C$_{60}$ and forms endohedral supramolecular complex H$_2$@C$_{60}$. In this confinement hydrogen acquires new properties. Its translational motion becomes quantized and is correlated with its rotations. We applied infrared spectroscopy to study the dynamics of hydrogen isotopologs H$_2$, D$_2$ and HD incarcerated in C$_{60}$. The translational and rotational modes appear as side bands to the hydrogen vibrational mode in the mid infrared part of the absorption spectrum. Because of the large mass difference of hydrogen and C$_{60}$ and the high symmetry of C$_{60}$ the problem is identical to a problem of a vibrating rotor moving in a three-dimensional spherical potential. The translational motion within the C$_{60}$ cavity breaks the inversion symmetry and induces optical activity of H$_2$. We derive potential, rotational, vibrational and dipole moment parameters from the analysis of the infrared absorption spectra. Our results were used to derive the parameters of a pairwise additive five-dimensional potential energy surface for H$_2$@C$_{60}$. The same parameters were used to predict H$_2$ energies inside C$_{70}$[Xu et al., J. Chem. Phys., {\bf 130}, 224306 (2009)]. We compare the predicted energies and the low temperature infrared absorption spectra of H$_2$@C$_{70}$.Comment: Updated author lis

Small molecule activation

The activation of small molecules has become an increasingly popular area of research over the last years, and there are many reasons to be captivated by this fascinating topic

Application of Transition Metal Catalysis to Small Molecule Synthesis

Over the past decade, transition metal catalysis has developed into a new field in organic synthesis, enabling numerous synthetic transformations that were previously not feasible. This thesis describes the application of both ruthenium and rhenium catalysis to the synthesis of several classes of small molecules. Ruthenium-catalyzed ring-opening cross-metathesis of five- through eight-membered ring cycloolefins was investigated for the synthesis of functionalized dienes (Chapter 1). Unsubstituted, trisubstituted, and allyl-substituted cycloolefins were studied. Regioselective reactions could be achieved with the use of unsymmetrical cycloolefins. Ruthenium-catalyzed cross-metathesis was explored for the synthesis of both di- and trisubstituted vinyl boronates (Chapter 2). These reactions proceeded efficiently for a wide variety of functionalized alkenes and generally exhibited high E-stereoselectivity. The resultant vinyl boronate products were stereoselectively converted into both Z-vinyl bromides and E-vinyl iodides. The rhenium-catalyzed 1,3-isomerization of allylic alcohols was employed in the synthesis of various allylic alcohols (Chapter 3). Two different strategies were developed to promote high product selectivity in these reactions: conjugated product synthesis and N,O-bis(trimethylsilyl)acetamide-promoted product trapping. These reactions enabled the synthesis of allylic alcohols with conjugated or non-conjugated, di- or trisubstituted, and electron-rich or electron-deficient alkene components. Partial chirality transfer was observed during the 1,3-isomerization of certain enantioenriched allylic alcohols. The fundamental reaction properties observed during these studies were all consistent with the operation of a mechanism involving a chair-like transition state, which contains a partially cationic allyl moiety, as the primary reaction pathway

Genome-scale architecture of small molecule regulatory networks and the fundamental trade-off between regulation and enzymatic activity

Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. Generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.P30 CA008748 - NCI NIH HHS; R01 GM121950 - NIGMS NIH HH

Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53