Showing papers by "Ronald Breslow published in 2015"

Creation of a histone deacetylase 6 inhibitor and its biological effects

Abstract: We report the development of a potent, selective histone deacetylase 6 (HDAC6) inhibitor. This HDAC6 inhibitor blocks growth of normal and transformed cells but does not induce death of normal cells. The HDAC6 inhibitor alone is as effective as paclitaxel in anticancer activity in tumor-bearing mice.

Evidence for tunneling in base-catalyzed isomerization of glyceraldehyde to dihydroxyacetone by hydride shift under formose conditions

Abstract: Hydrogen atom transfer reactions between the aldose and ketose are key mechanistic features in formose chemistry by which formaldehyde is converted to higher sugars under credible prebiotic conditions. For one of these transformations, we have investigated whether hydrogen tunneling makes a significant contribution to the mechanism by examining the deuterium kinetic isotope effect associated with the hydrogen transfer during the isomerization of glyceraldehyde to the corresponding dihydroxyacetone. To do this, we developed a quantitative HPLC assay that allowed us to measure the apparent large intrinsic kinetic isotope effect. From the Arrhenius plot of the kinetic isotope effect, the ratio of the preexponential factors A H / A D was 0.28 and the difference in activation energies E a(D) − E a(H) was 9.1 kJ·mol −1 . All these results imply a significant quantum-mechanical tunneling component in the isomerization mechanism. This is supported by multidimensional tunneling calculations using POLYRATE with small curvature tunneling.

Magnesium pyrophosphates in enzyme mimics of nucleotide synthases and kinases and in their prebiotic chemistry

Abstract: Derivatives of ribosyl pyrophosphate have been synthesized, and examined with magnesium salts in the coupling of the ribose unit to various nucleophiles, including pyrazole and 2-chloroimidazole. Only with the magnesium salt present did they generate the ribosyl cation by binding to the leaving group and then couple the ribose derivative with nucleophiles. The role of magnesium salts in phosphorylation of methanol by ATP was also examined. Here a remarkable effect was seen: phosphorylation by ATP was slowed with low concentrations of Mg 2+ but accelerated by higher concentrations. Related effects were also seen in the effect of Mg 2+ on phosphorylation by ADP. The likely mechanisms explain these effects.

Novel Aromatic and Antiaromatic Systems

Abstract: Note from the Editor: August Kekule's dream and his theory of the structure of benzene (1865). Julius Thomsen's logic that benzene contains equivalent electrons between its carbon atoms (ca. 1900). Richard Willstatter's synthesis and observation that 1,3,5,7-cyclooctatetraene is not aromatic (early 1900s). Sir Robert Robinson's proposal of the ‘aromatic sextet’ (1925). Erich Huckel's molecular orbital treatment of benzene and other unsaturated compounds that separated sigma and pi electrons (early 1930s). Tetsuo Nozoe and Michael Dewar's independent proposal of a new aromatic structure for a cycloheptatrieneone (mid-1940s). Ronald Breslow's demonstration that cyclopropenyl cation is aromatic (1958). Breslow's proposal of ‘antiaromaticity’ (1965). I offer several comments. First, in the field of aromaticity, Breslow is in mighty exceptional company. Second, his research has extended well beyond aromaticity. Yes, Breslow is applying the concepts of antiaromaticity toward the development of highly conductive organic materials. But his research has encompassed enzyme mimics, remote functionalization reactions, unnatural DNA analogues and cancer chemotherapy. Indeed, Breslow is the co-discoverer of a highly successful drug, Vorinostat, which is FDA-approved for the treatment of cutaneous T-cell lymphoma. We thank Professor Breslow for joining our project honoring his and our friend, Tetsuo Nozoe. Tetsuo Nozoe would have would have been deeply touched. —Jeffrey I. Seeman Guest Editor University of Richmond Richmond, Virginia 23173, USA E-mail: jseeman@richmond.edu Ronald Breslow with Koji Nakanishi (left) and Tetsuo Nozoe (center), Sendai, 1970. Abstract We contributed to the field of non-benzenoid aromatic compounds by creating the cyclopropenyl cation and various of its derivatives, including cyclopropenone; it was the first aromatic system with other than six pi electrons in a single ring, and the simplest aromatic system. The pioneering work of Tetsuo Nozoe in tropolone chemistry was celebrated with the founding of ISNA, the International Symposium on Non-Benzenoid Aromatic Compounds, where I described our work in the field. It fit the prediction that aromaticity would be found in systems with 4n + 2 pi electrons, where n is an integer. I was also concerned with the properties of monocyclic systems with 4n cyclically conjugated pi electrons. They were expected not to be aromatic, but the interesting question was whether they were actually antiaromatic, especially destabilized by the cyclic conjugation in such 4n species as the cyclopropenyl anion, cyclobutadiene, and cyclopentadienyl cation. The evidence supports antiaromaticity in these cases. We also examined compounds where 4n cyclic pi systems were fused with aromatic systems, and most interestingly systems in which two 4n pi systems were fused. In these cases the periphery of the molecules had 4n + 2 pi electrons, for aromaticity, but the components were antiaromatic. Recently we have studied electrical conductivities in aromatic molecules such as thiophene and saw that aromaticity added resistance to the systems, so non-aromatic compounds are better conductors and antiaromatic compounds are predicted to be the best of all.