A squaraine dye with bulky end groups is employed as the thread component in two Leigh-type amide rotaxanes. The rotaxanes are synthesized in a simple two-step process. X-ray crystal structures of the rotaxanes show that the pyridyl-containing macrocycle is more rigid and wraps more tightly around the cyclobutene core of the squaraine thread compared to the isophthalamide-containing macrocycle. The rotaxanes exhibit photophysical properties that are similar to the precursor squaraine. The encapsulating macrocycle greatly increases the chemical stability of the squaraine thread and inhibits aggregation-induced broadening of its absorption spectrum. It should be possible to prepare squaraine-derived rotaxanes with improved properties for a wide range of photophysical, photochemical, and biomedical applications.

There is a demand for new methods of protecting organic dyes from aggregation effects and photochemical degradation. The purpose of this microreview is to summarize the recent attempts to improve the properties of dyes by molecular encapsulation. Organic dyes have been encapsulated inside inorganic matrices such as molecular sieves, and molecular containers such as cyclodextrins, cucurbiturils, dendrimers, and self-assembled gels. Another strategy is perma- IntroductionOrganic chromophores such as cyanines, squaraines, azo dyes and perylenediimide dyes are widely used as pigments in many commercial products. They are active ingredients in semiconducting materials, [1] textile products, [2] laser materials, [3] optical disks, [4] paints, [5] and probes for biological systems.[6] Modern research on organic dyes includes investigations of building blocks for conjugated polymers, hydrogen bonded assemblies, chromogenic sensors, molecular shuttles, solar energy cells, photonics and various approaches to photodynamic therapy. [7][8][9][10][11] A common limitation with organic dyes, especially those with long-wavelength absorption bands, is their susceptibility to chemical and photochemical degradation. The reason for the enhanced reactivity is the inherently small HOMO-LUMO energy gap, which means that the dyes are potentially reactive with both nucleophiles and electrophiles. Another potential drawback with organic dyes is their tendency to aggregate, which induces multichromophoric interactions that alter the color quality and quench the photoluminescence. In principle, these problems can be attenuated by supramolecular encapsulation strategies that isolate the individual dye molecules and prevent self-aggregation or similar interactions with the chemical environment. The purpose of this microreview is to summarize the recent literature on meth- Germany, 2005) ods to improve the properties of organic dyes by molecular encapsulation. The focus is on relatively "robust" molecular containers and does not include "soft" assemblies like micelles, emulsions or vesicles.

(4-Phenoxyphenylsulfonyl)methylthiirane (inhibitor 1) is a highly selective inhibitor of gelatinases (matrix metalloproteinases 2 and 9), which is showing considerable promise in animal models for cancer and stroke. Despite demonstrated potent, selective, and effective inhibition of gelatinases both in vitro and in vivo, the compound is rapidly metabolized, implying that the likely activity in vivo is due to a metabolite rather than the compound itself. To this end, metabolism of inhibitor 1 was investigated in in vitro systems. Four metabolites were identified by LC/MS-MS and the structures of three of them were further validated by comparison with authentic synthetic samples. One metabolite, 4-(4-thiiranylmethanesulfonylphenoxy)phenol (compound 21), was generated by hydroxylation of the terminal phenyl group of 1. This compound was investigated in kinetics of inhibition of several matrix metalloproteinases. This metabolite was a more potent slow-binding inhibitor of gelatinases (matrix metalloproteinase-2 and matrix metalloproteinase-9) than the parent compound 1, but it also served as a slow-binding inhibitor of matrix metalloproteinase-14, the upstream activator of matrix metalloproteinase-2.

Abstract(±)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase (MMP) family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiiraneopened 1, will possess potent MMP inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable K i of 530 pM against MMP-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases. Keywords thiirane; latent thiolate; zinc protease; tight-binding inhibitionThe central position of the epoxide ring in organic synthesis derives from the ease of its synthesis, and the ability of Brønsted or Lewis acids to control its opening by nucleophiles. Thiiranes, three-membered rings containing a sulfur atom, are typically less reactive than epoxides. Due to their latent reactivity toward nucleophiles, the aziridines, epoxides and thiiranes all have been used as irreversible enzyme inhibitors (1-3). In the pioneering work of Kim et al., epoxybutanoic acid covalently modified the carboxylate of the glutamate in the active site of the zinc protease, carboxypeptidase A (4). The catalytic zinc ion of this protease, which activates the scissile amide bond of the substrate during normal turnover, here functions as a Lewis acid for epoxide O-alkylation of this glutamate (5). The conceptual extension of this principle to the creation of efficacious matrix metalloproteinase inhibitors, zinc proteases involved in the pathophysiology of inter alia human inflammation and tumor metastasis, is an objective of this laboratory (6). We previously reported the discovery, the core SAR, and initial computational and experimental mechanistic studies with the thiirane-containing structure 1 (7-12). Thiirane 1 (also known as SB-3CT) exerts * Corresponding author: Shahriar Mobashery, mobashery@nd.edu. Supporting InformationAdditional Supporting Information may be found in the on-line version of this article: enzymatic assay methods, computational methods, and synthetic procedures. NIH Public Access Author ManuscriptChem Biol Drug Des. Author manuscript; available in PMC 2010 December 1. (25), and T-cell lymphoma metastasis to the liver (26). In contrast, the lack of efficacy of 1 in cell culture models of ovarian cancer cell metastasis implicates the activity of other MMPs during collagen degradation in this cancer (27). The favorable biological outcome in MMP-dependent disease models using 1 as a gelatinase MMP subclass inhibitor stimulated this further mechani...

The barrier for rotation about an N-alkylcarbamate C(carbonyl)-N bond is around 16 kcal/mol. In the case of an N-phenylcarbamate, the rotational barrier is lowered to 12.5 kcal/mol, but with N-(2-pyrimidyl)carbamates the barriers are so low (<9 kcal/mol) that the syn and anti rotamers cannot be observed as separate signals by 500 MHz NMR spectroscopy at 183 K. X-ray and computational data show that the N-(2-pyrimidyl) carbamates have C(carbonyl)-N bonds that are on average 0.03 A longer than for related N-phenylcarbamates. The computational results trace the origin of the effect to increased single bond character for the C(carbonyl)-N bond due to the increased electron-withdrawing ability of the pyrimidyl ring.