Introduction. The matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes that are capable of degrading many proteinaceous components of the extracellular matrix. 1 The enzymes have been implicated in several pathological processes including arthritis, 2, 3 tumor growth and metastasis, 4 periodontal disease, 5 and multiple sclerosis. 6 Considerable research has been devoted to the discovery of potent MMP inhibitors which may act as potential diseasemodifying agents in a number of important pathologies. 7 The phase II pancreatic cancer clinical trial data obtained with Marimastat, the most clinically advanced MMP inhibitor, has now been reported. 8, 9 The hydroxamic acid-based MMP inhibitors have been by far the most extensively studied class of inhibitors due to the ability of the hydroxamate group to efficiently complex the catalytic zinc and also to develop two hydrogen bonds to Glu-202 and Ala-165. 10 In addition to binding to the catalytic zinc, the hydroxamate-based MMP inhibitors require several more binding interactions for potent inhibition of the target enzymes. The S1′ and S2′ pockets have been extensively used for this purpose. While the design of MMP inhibitors is gradually becoming less complex, the chirality of such molecules demands extensive use of the chiral pool and/or stereoselective synthetic methods for their preparation. Structures of several MMP inhibitors that have progressed to early stages of clinical trial can serve as illustrative examples (see Chart 1). 11 We believed that the design of MMP inhibitors could be simplified by the introduction of a plane of symmetry. Such an approach also offered the potential for developing favorable binding at the S1 pocket. Indeed, this design, when applied to the sulfonamide-based MMP inhibitors, 11f has led to the discovery of a novel series of simple, nonchiral, and potent in vitro inhibitors of the matrix metalloproteinases. 12, 13

Chemistry. The synthesis of the MMP inhibitors was considerably simplified by the symmetry of the target molecules (see Scheme 1). Typically, a commercially available R, ω-diaminoalkane 1 was converted to the corresponding bis-sulfonamide 2 under the standard acylation conditions. In the next step the 1, 3-diaza ring was formed by condensation of 2 with methyl glyoxalate polymer under the catalysis of sulfuric acid. Water formed during this reaction was removed via azeotropic distillation. The methyl ester 3 was then subjected to basic hydroxylamine solution14 to provide the target hydroxamic acid 4 in 40r70% overall yield. X-ray crystallography data15 obtained for compound 4e (see Figure 1, top) confirmed the desired structure and symmetry of this series of MMP inhibitors. Compound 4e was found to assume a chair conformation with the two methoxyphenylsulfonyl groups in equatorial positions and the hydroxamic acid group in an axial position. The arylsulfonyl groups were located in a trans relationship to each other.