Graham J. Tizzard

Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

N1-Hydroxy-N8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC50 = 2.4 μM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (μM, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

Click JAHAs: conformationally restricted ferrocene-based histone deacetylase inhibitors

A small library of ferrocene-based 1,2,3-triazole-containing hydroxamic acids has been synthesised employing click chemistry: 7-(4-ferrocenyl-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide, 4b, containing the 1,2,3-triazole moiety adjacent to the ferrocene group, displayed excellent HDAC inhibition and activity in cells, inhibiting the deacetylation of tubulin as well as inducing cell cycle arrest.

Synthesis of a Class of Core-Modified Aza-BODIPY Derivatives

The convenient synthesis of a new class of conjugated aza-BODIPY derivatives from readily available precursors has been achieved. The new materials bear close structural similarity to BODIPYs but differ significantly in electronic configuration from known derivatives, leading to markedly different absorption and emission properties.

Synthesis, characterization, MCD spectroscopy, and TD-DFT calculations of copper-metalated nonperipherally substituted octaoctyl derivatives of tetrabenzotriazaporphyrin, cis- and trans-tetrabenzodiazaporphyrin, tetrabenzomonoazaporphyrin, and tetrabenzoporphyrin.

Synthesis of the title compounds has been achieved through refinement of a recently reported synthetic protocol whereby varying equivalents of MeMgBr are reacted with 1,4-dioctylphthalonitrile to produce mixtures favoring specific hybrid structures. The initially formed magnesium-metalated compounds are obtained as pure materials and include, for the first time, both isomers (cis and trans) of tetrabenzodiazaporphyrin. The compounds were demetalated to the metal-free analogues, which were then converted into the copper-metalated derivatives. The X-ray structure of the copper tetrabenzotriazaporphyrin derivative is reported. The metal-free and copper-metalated macrocycles exhibit columnar mesophase behavior, and it is found that the mesophase stability is unexpectedly reduced in the diazaporphyrin derivatives compared to the rest of the series. The results of time-dependent density functional theory calculations for the copper complexes are compared to the observed optical properties. Michls perimeter model was used as a conceptual framework for analyzing the magnetic circular dichroism spectral data, which predicted and accounted for trends in the observed experimental spectra.

Chiral 2,6-lutidinyl-biscarbene complexes of palladium

Chiral complexes of palladium, 1, with the new tridentate ‘pincer’ ligand 2,6-lutidinyl-biscarbene (C⁁N⁁C), have been prepared; in the solid state they exhibit helical C2 symmetrical structures which are persistent in solution at least up to 80 °C; the chiral nature of 1 has been established by NMR methods using Pirkle’s acid as a chiral discriminating agent; racemic mixtures of 1 are highly active catalysts in Heck coupling reactions.

2-Amidoindole-based anion receptors

Four receptors containing either 2-amidoindole or 7-nitro-2-amidoindole groups have been synthesised and shown to complex oxoanions in DMSO-d 6/0.5% water solution. X-ray crystal structure elucidation reveals that receptor 1 complexes dihydrogen phosphate ion pairs in the solid state, which are part of a continuous chain. While this receptor binds dihydrogen phosphate in a 1:1 stoichiometry in solution, compound 4, which contains 7-nitroindole groups, does form 1:2 receptor:dihydrogen phosphate complexes in DMSO-d 6/0.5% water.

Intriguing relationships and associations in the crystal structures of a family of substituted aspirin molecules

A number of ring-substituted aspirin molecules have been synthesised and their crystal structures determined. All contain the strongly H-bonded carboxylate dimer found in the two forms of aspirin itself. Detailed analysis of the further packing of this dimer reveals that the 5-chloro, 5-bromo and 5-iodo derivatives form an isostructural group, as do the 5-fluoro, 5-methyl and 5-nitro derivatives. The 3-methyl and 4-methyl structures have close 3D similarity and may be classified as pseudoisostructural. The structures of the first two groups have a common 1D stack of dimers which contributes to two different 2D layers. One of the 2D layers is found in the fluoro, nitro and 5-methyl isostructures and also in the 3-methyl and 4-methyl derivatives. The second layer motif is found in the chloro, bromo and iodo groups and is also present in the fluoro, nitro and 5-methyl structures. The 6-methyl structure shares a 1D motif with the chloro, bromo and iodo groups. The packing variations are linked to different types of intermolecular interactions. In the 5-Cl, Br, and I groups, we find short Hal⋯O contacts to the carboxylate carbonyl; in the 5-F, 5-NO2 and 5-Me derivatives we find the acyl⋯acyl dimer interaction, present also in aspirin form I. In addition, the 5-F structure contains F⋯O short contacts to a carboxylate hydroxyl oxygen and in the 5-NO2 we find N–O⋯H–C contacts to an acyl methyl group.

Expanded Porphyrin-like Structures Based on Twinned Triphenylenes

Triphenylene twins are intriguing structures, and those bridged through their 3,6-positions by dipyrromethene units give a new class of macrocycles that can be viewed as rigid, expanded porphyrin derivatives in which coplanarity is enforced in a formally antiaromatic π system. Somewhat surprisingly, however, macrocyclization leads to significant overall stabilization of the dipyrromethene chromophores.

Synthesis of meso‐Substituted Tetrabenzotriazaporphyrins: Easy Access to Hybrid Macrocycles

Up to now, hybrid structures that lie between the ubiquitous phthalocyanine and porphyrin scaffolds have been extremely difficult to prepare. A straightforward, high yielding synthesis of meso-derivatized tetrabenzotriazaporphyrins (see scheme) is described, thus unlocking access to this underdeveloped class of materials.

Screening for polymorphs on polymer microarrays.

ReceiVed June 29, 2007 Introduction. The way in which compounds crystallize has been the subject of study for many centuries with perhaps the most classical example relating to tartaric acid. A current focal point in this area is the phenomenon of polymorphism. This arises because of two main considerations; first in terms of patent law, new crystal forms of a solid compound can be considered as innovations and can be protected as intellectual property (this crucial issue has promoted the intense search for new polymorphs). Second, and of more practical consideration, is the fact that specific crystal forms can alter the dissolution rate of a compound, and thus, the pharmokinetics of any drug are partially determined by the specific crystal form, an issue that also supports the patentability of a polymorph. Many polymorphs have been discovered serendipitously, but traditional methods of discovery and selection of polymorphic forms usually involve the variation of crystallization parameters such as temperature and solvent, and current high-throughput screens generally rely on variation of these parameters. Examples of well-known compounds for which new polymorphic forms have been discovered, after many years of work, include maleic acid (120 years after it was first crystallized) and aspirin, confirming McCrone’s often quoted pronouncement. However, fewer than 5% of compounds in the Cambridge Structural Database are reported to be polymorphic, whereas it is known from other studies that do not provide a full structure (e.g., spectroscopic, thermal, and microscopy studies) that more than 35% of known compounds show polymorphic behavior. Therefore new developments in high-throughput platforms for primary polymorph screening would be a valuable tool for the discovery of, as yet, uncharacterized forms. The substrates upon which crystals grow play a pivotal role in allowing selective growth. For example, calcium carbonate crystal growth can be easily “tuned” by interaction with different surfaces, allowing a range of specific structures to be generated. Organic compounds, however, are typically difficult to tune because their “packing” is much more temperamental. In the approach presented here, control over specific factors involved in the crystallization processes such as concentration and temperature were used, but the main variable was the surface upon which crystallization occurred. It is well-known that polymers can support the growth of specific types of crystals. However, the nature of the interactions between the polymer and the compound under investigation are not understood, and it is not possible to predict the specific polymorphic form generated by crystallization on a specific polymeric support. The technique described here provides a tool to better understand these types of interactions, as well as to reduce the amount of material needed to carry out a “fullpolymorphic screen”. The approach developed, related to that described by Kazarian, used polymer microarrays onto which solutions of small-molecules were applied and allowed to crystallize, which because of the size of the arrays, required only tiny amounts of solution. The resultant crystals underwent direct characterization on the microarray by optical and Raman microspectroscopy (Raman spectroscopy has been proven to be a valid tool to differentiate between polymorphic forms.). It should be noted that even though different crystal habit forms were found within the array these did not always correspond to different polymorphic forms according to Raman shifts. In general, organic materials tend to crystallize in less symmetric space groups than inorganic materials, a phenomenon which makes crystal habit a less efficient indicator of different polymorphic forms in organic materials than it is for inorganic materials. The first step in the process consisted of fabrication of the polymer microarrays. This approach consisted of hydrophobic patterning of a glass slide into three grids, each consisting of 8 × 16 hydrophilic “features”. A specific polymer was then deposited by piezo jet-printing 800 drops of each of the polymer solutions onto a specific hydrophilic feature (each drop was ∼30 μm in diameter, and therefore, ∼0.9 μL of a 1% polymer solution was deposited, equating to approximately 9 μg of polymer per spot). The polymers used in this study were synthesized or obtained commercially (see Supporting Information for full experimental details). Two solvents were used for inkjet printing: NMP and toluene. NMP was the dominant solvent used because it efficiently dissolved the majority of the library of polymers, whereas toluene was used for the more hydrophobic polymers (see Supporting Information). Each slide thus contained three 8 × 16 grids giving a total of 128 polymer spots with the area of each spot approximately 1.76 mm. Three well-known and broadly studied small molecules were used in this study: carbamazepine, sulfamethoxazole, and 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (often termed ROY (red/orange/yellow) from the well-known colors of the different polymorphic forms). This choice was the result of the large number of polymorphic studies previously carried out on these compounds, which allowed us to compare our approach to previous reports. Mother liquors of the small molecules were printed onto the polymer * To whom correspondence should be addressed. Phone: +44(0) 131 650 4820. Fax: +44 (0) 131 650 6453. E-mail: Mark.bradley@ed.ac.uk. † University of Edinburgh. ‡ University of Southampton. J. Comb. Chem. 2008, 10, 24–27 24