Surprising Chemistry of 6-Azidotetrazolo[5,1-a]phthalazine: What a purported natural product reveals about the polymorphism of explosives

6-Azidotetrazolo[5,1-a]phthalazine (ATPH) is a nitrogen-rich compound of surprisingly broad interest. It is purported to be a natural product, yet is closely related to substances developed as explosives and is highly polymorphic despite having a nearly planar structure with little flexibility. Seven solid forms of ATP have been characterized by single-crystal X-ray diffraction. The structures show diverse patterns of molecular organization, including both stacked sheets and herringbone packing. In all cases, N···N and C–H···N interactions play key roles in ensuring molecular cohesion. The high polymorphism of ATPH appears to arise in part from the ability of virtually every atom of nitrogen and hydrogen in the molecule to take part in close N···N and C–H···N contacts. As a result, adjacent molecules can adopt many different relative orientations that are energetically similar, thereby generating a polymorphic landscape with an unusually high density of potential structures. This landscape has been explored in detail by computational prediction of crystal structures. Studying ATPH has provided insights about the field of energetic materials, where access to multiple polymorphs can be used to improve performance and clarify how it depends on molecular packing. In addition, our work with ATPH shows how valuable insights about molecular crystallization, often gleaned from statistical analyses of structural databases, can also come from in-depth empirical and theoretical studies of single compounds that show distinctive behavior

Non-Natural Macrocyclic Inhibitors of Histone Deacetylases: Design, Synthesis, and Activity

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors