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Malignant transformation of melanocytes is associated with changes in melanogenesis. Therefore, fluorescence of melanin may be an informative indicator of this process. But the conventionally excited autofluorescence of melanin in skin tissue is ultra-weak and its main part in the visible spectral region is hidden by the much stronger fluorescence from other endogenous fluorophores. Here, using a new mode of stepwise two-photon excitation, melanin-dominated fluorescence spectra of pigmented skin lesions are reported. From these, pure melanin fluorescence spectra of normal pigmented skin, melanocytic nevi and malignant pigmented melanoma were analyzed. They show distinctly different spectral shapes: melanoma gave a characteristic fingerprint with a fluorescence band peaking at 640 nm, independent of the melanoma subtype. The melanin fluorescence spectra peaked at 590 nm for all types of common melanocytic nevi. These differences in the fluorescence spectra are probably based on different contents of eumelanin and pheomelanin. In a series of 167 cases with melanocytic nevi and melanomas, the sensitivity of this new method to diagnose melanoma was 93.5%, the specificity 80.0% and the diagnostic accuracy 82.6%. The two-photon excitation fluorescence method is a new diagnostic tool which may in future supplement conventional dermatohistopathology.

Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in a remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore exhibiting properties which are also highly beneficial for its introduction into other inhibitor classes.

Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells.

Because of the increasing incidence of skin cancer, interest in using the autofluorescence of skin tissue as a noninvasive tool for early diagnosis is enforced. Focus is especially on malignant melanotic melanoma. On the basis of a newly developed method to selectively excite melanin fluorescence of skin tissue by stepwise two-photon excitation with nanosecond laser pulses at 810 nm, we have investigated information from this melanin fluorescence with respect to the differentiation of pigmented lesions. A distinct difference in the melanin fluorescence spectrum of malignant melanoma (including melanoma in situ) when compared to that of benign melanocytic lesions (i.e., common nevi) has been found for freshly excised samples as well as for histopathological samples. There is also specific fluorescence from dysplastic nevi. In this way, early detection of malignant melanoma is possible.

A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.

Aspirin, the acetyl ester of salicylic acid, was first discovered in the late 1800s and became one of the most world-renowned drugs. Its fame is rooted in its ability to treat a wide range of symptoms such as fever, inflammation, and pain. Aspirin represents an advancement of the previously applied salicylic acid, which was obtained from myrtle leaf decoction or willow bark extract, but was found to be less active and to cause serious gastrointestinal irritation.[1] Later on, other chemical modifications of aspirin were investigated with the aim of improving its pharmacological profile. The influence of additional substituents on the phenyl ring and modification of the acetoxy and carboxy groups were studied, [2] and even the phenyl core of aspirin was replaced by the organometallic ferrocene moiety. [3] However, none of these derivatives could substitute for aspirin. We have now modified aspirin by replacing the phenyl ring with a three-dimensional and highly hydrophobic carbaborane cluster.Carbaboranes are already known in medicinal chemistry as phenyl group mimetics, and analogues of tamoxifen, [4] trimethoprim, [5] and transthyretin amyloidosis inhibitors derived from flufenamic acid and diflunisal, [6] two nonsteroidal anti-inflammatory drugs (NSAIDs), have been presented.The focal point of our research was a high-yield synthesis of asborin, the carbaborane analogue of aspirin, and the study of its pharmacological behavior. Asborin is obtained in three steps (Scheme 1) starting from ortho-dicarba-closo-dodecaborane(12) (1). In the first step one of the carbaborane carbon atoms is hydroxylated according to a protocol described by Endo and co-workers.[7] The monolithiated carbaborane is treated with trimethyl borate to give a carbaboranyl boronic ester in situ. The ester is then oxidized with peracetic acid. The second step is carboxylation of the second cluster carbon atom. Both the OH proton and the remaining carbaborane CH proton of 2 can be removed with n-butyllithium, and reaction of the resulting dilithium salt with gaseous carbon dioxide gives 1-hydroxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (3) in greater than 99 % yield after acidic workup. Compound 3, with an ortho arrangement of hydroxy and carboxy groups, is the carbaborane analogue of salicylic acid. Finally, 1-acetoxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (asborin, 4) is obtained quantitatively simply by stirring 3 in acetyl chloride. The use of acetyl chloride rather than acetic anhydride is advantageous, as it can easily be removed under reduced pressure due to its lower boiling point of 52 8C. Crystals of 4 suitable for X-ray crystallography ( Figure 1) were obtained from chloroform; hydrogen-bonded dimers are formed via the carboxy groups.Asborin, with its hydrophobic cluster framework and hydrophilic carboxy group, is remarkably amphiphilic: It dissolves in water and nonpolar organic solvents.Aspirin is one of the smallest members of the NSAID family. These compounds are structurally very diverse, but all of the...

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