In rheumatoid and osteoarthritis, degradation of articular cartilage is mediated by the matrix metalloproteinases collagenase, stromelysin and gelatinase. The key event in this process is the cleavage of triple helical collagen by collagenase. We have determined the crystal structure of the catalytic domain of human recombinant fibroblast collagenase complexed with a synthetic inhibitor at 2.2 A resolution. The protein fold is similar to the amino termini of the zinc endopeptidases astacin thermolysin and elastase despite a lack of primary sequence homology. The conformation of the bound inhibitor provides a molecular basis for the design of inhibitors of collagenase and other matrix metalloproteinases. Such inhibitors should be useful in the treatment of a variety of diseases including arthritis and cancer.
Rational syntheses are described of a number of new 22 x-electron macrocycles containing pyrrole, furan, and thiophen rings and one or two direct links. A further example of the sulphur extrusion process applied to macrocycle synthesis is provided. N.m.r. studies are used to show that all the macrocycles are aromatic, and they all contain intense Soret type bands in their visible spectra. The dioxasapphyrin does not form metal complexes and shows remarkable rate differences in the electrophilic deuteriation of the meso-positions. PREVIOUS work on the synthesis of dioxacorroles (1) led to the isolation of a by-product tentatively formulated as the 22 x-electron macrocycle (2).2 This result, together with a general interest in the aromaticity of large macrocycles, prompted the study of methods for the rational synthesis of pyrrolic 22 x-electron macrocycles and related systems. The only reported example of this class of compound at the outset of our work was the all-pyrrole analogue of (2), named sapphyrinJ3 for which details of the synthesis are not available.Our initial work was directed towards a synthesis of the dioxasapphyrin system, to confirm the structure of the by-product (2) isolated previously. A general method for the construction of sapphyrin-type macrocycles was developed involving the condensation of a two-ring component (3) with a bis(pyrrolylmethy1) -pyrrole diacid (4). Thus acid-catalysed condensation of compounds (3; X = 0, R1 = R2 = H) and (4) followed by oxidation with either air or iodine gave the dioxasapphyrin (i,"), which was shown to be a single isomer by n.m.r. spectroscopy. The dioxasapphyrin (2) had an electronic spectrum identical with that of the by-product isolated previously,l and the n.m.r. spectra were similar. The synthesis of a representative sapphyrin [i.e. (5)] was also undertaken, to compare the properties of the macrocycles. Suitable two-ring precursors would be the difonnylbipyrroles, and despite our earlier failure to prepare the difonnylalkylbipyrroles (3; X = NH, R1 = R2 = Me and R1 = Me, R2 = Et) we have now succeeded in preparing these compounds in good yield (>60y0) by Vilsmeier-Haack formylation of the corresponding 5,5'-unsubstituted bipyrroles with an excess of fonnylating reagent at 100". The solubility of diformylalkylbipyrroles in organic solvents is low but the condensation of compounds (3; X = NH, R1 = Me, R2 = Et) and (4) could be successfully carried out in chloroform or chloroform-methanol to give the sapphyrin (5) (46%). A further example of this type of macrocycle, a thiasapphyrin (6), has also been prepared (19.570), by the condensation of the bipyrrole (3; X = NH, R1 = Me, R2 = Et) and the dipyrrolylthiophen (7). Although the yields in these condensation reactions are not particularly high, they are perhaps remarkably better than might have been anticipated in view of the size of ring being produced. Presumably intramolecular hydrogen bonding between pyrrole rings results in conformations beneficial to the cyclisation process. Finally, our recently deve...
The preparation of 21 -oxa, 21 -thia-, 21,23-dioxa-, 21,23-dithia-, and 21 -oxa-23-thia-porphins is described.tThese new porphin analogues have spectral properties similar to those of the porphins. which supports their formulation as aromatic macrocycles. Surprising basicity is displayed by 21.22-and 21.23-dioxaporphins and unusual mass spectra are produced by the oxaporphins. Only the 21 -oxa-and 21 -thia-porphins form metal complexes under the usual conditions used for rnetalloporphin formation. The results of deuterium exchange studies on the new macrocycles are reported.METAL complexes of porphins and dihydroporphins theoretical and experimental study. The porphins
The preparation of 21.24-dioxacorroles by condensation of dipyrromethane-5,5'-dicarboxylic acids with 5,5'-diformyl-2.2'-bifuryl or bis-(5-formyl-2-furyl) sulphide is described. It is suggested that the latter reaction involves a non-aromatic meso-thia-macrocyclic intermediate which loses sulphur by a disrotatory cyclisation to a thiiran intermediate followed by cheletropic loss of sulphur. Some evidence for this proposal is provided by the preparation of meso-thiaphlorins and a study of their thermolyses to give corroles. Further examples of sulphur extrusion from a meso-dithiaphlorin, to give a meso-thiacorrole, are given and rate enhancements, in the sulphur extrusion process, which are observed in metal complexes are discussed. Some electrophilic deuteriation studies on the 21,24-dioxacorroles are reported.
, p.o., inhibited degradation of articular cartilage in a rat monoarthritis model induced by an intra-articular injection of Propionibacterium acnes. 6 Ro 32-3555 is a potential therapy for the treatment of the chronic destruction of articulating cartilage in both rheumatoid and osteoarthritis.
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