For hydroxypyrone inhibitors, only inhibitors with backbones at the 2-position (e

For hydroxypyrone inhibitors, only inhibitors with backbones at the 2-position (e.g., 3, 4, and AM-2) were selective against MMP-3 over MMP-1 and MMP-2; and all 5- and 6-backbone hydroxypyrones 9aCb, 14aCb, and 15 were overall less potent for all MMPs and generally lacked isoform selectivity. tris(histidine)-bound zinc(II) ion. The protein matrix surrounding the zinc center is comprised of a series of subsite pockets designated as S1, S2, S3, S1, S2, and S3 (Fig. 1). The different structures of the MMP subsites, and the amino acids comprising those subsites, lead to substrate selectivity for different MMP isoforms. MMPs are involved in tissue remodeling, wound healing, and growth. The misregulated activities of these enzymes are also implicated in a variety of diseases such as cancer, arthritis, atherosclerosis, and heart disease.1C3 Thus, a number of investigations in both academia and industry have been carried out to develop MMP inhibitors (MMPi) as therapeutics to treat MMP-related diseases.1C4 A typical MMPi has Emcn two parts (Fig. 1): a zinc-binding group (ZBG) able to chelate a zinc(II) ion thus blocking the access N-Desethyl amodiaquine dihydrochloride of the substrate to the catalytic center, and a peptidomimetic backbone that provides non-covalent interactions with the subsite pockets thus tuning inhibitor potency and selectivity. Often in an MMPi a linking group (L) can also be defined that connects the backbone substituent to the ZBG. Most reported MMPi employ a hydroxamic acid as the ZBG with at N-Desethyl amodiaquine dihydrochloride least part of the backbone directed toward the S1 pocket.1C4 This strategy has been successful in providing potent MMPi, but hydroxamate inhibitors have limitations including in vivo hydrolysis and dose-limiting side effects. To overcome the drawbacks of hydroxamic acids, new MMPi with alternative ZBGs have been explored. Open in a separate window Figure 1 Schematic interactions between MMPs and MMP inhibitors. Hydroxypyrones and hydroxythiopyrones have versatile metal coordination chemistry.5C10 Among the most N-Desethyl amodiaquine dihydrochloride commonly studied hydroxypyrones are natural products maltol and kojic acid (Fig. 2), which are widely used as food and cosmetics additives, suggesting that they possess good biocompatibility.11 Hydroxypyrones have been explored for the development of new MMPi. Tris(pyrazolyl)borate zinc(II) complexes, used to mimic the MMP catalytic zinc(II) center, show that hydroxypyrones and hydroxythiopyrones can bind to the zinc(II) ion in a bidentate fashion.12 Maltol (hydroxypyrone) and thiomaltol (hydroxythiopyrone) are more effective ZBGs against MMP-3 (stromelysin) when compared to a simple hydroxamate ligand.13,14 Using hydroxypyrone as the ZBG, a series of potent and selective pyrone-based inhibitors of MMP-3 have been developed by attaching an aryl backbone to the 2-position of the pyrone ring.15,16 Simple hydroxythiopyrones have shown much higher inhibition activity (30C60 fold) than corresponding hydroxypyrones.14 This observation promoted us to explore the potential of a hydroxythiopyrone ZBG for development of full length MMP inhibitors. Unlike hydroxamate terminal chelators, in which the inhibitor backbone can only be extended in one direction, the hydroxypyrone ring has several positions (2-, 5-, an 6-) to attach backbones (Fig. 2). Hence, it is possible to develop novel hydroxypyrone-based inhibitors with multiple backbones to interact with MMP pockets (Fig. 1). In this report, we describe the syntheses of hydroxythiopyrone-based MMP inhibitors and their inhibition activities are compared with that of corresponding hydroxypyrones. The synthetic schemes for developing double-handed hydroxypyrone-based inhibitors have been explored. Hydroxypyrones and their hydroxythiopyrone analogues have also been widely reported in other biomedical applications such as iron balance in anemia and iron overload N-Desethyl amodiaquine dihydrochloride disorder,7,8 aluminium removal in Alzheimers disease,9,18,19 treatment of N-Desethyl amodiaquine dihydrochloride diabetes, 20C23 and contrast agents for medical imaging.24 As such, the synthetic studies and activity analysis provided here should be a valuable reference for development of new hydroxypyrones and hydroxythiopyrones for a wide range of medicinal applications. Open in a separate window Figure 2 Structures of hydroxamate, hydroxypyrone, and hydroxythiopyrone chelators. Previously, our laboratory has reported several potent and selective hydroxypyrone MMPi with aryl backbones at the 2-position. 15,16 Thus, we first synthesized corresponding 2-backbone hydroxythiopyrones and evaluated their inhibition activities (Scheme 1).15,16 Intermediate 1 was prepared according to a literature method.8 A coupling reaction of compound 1 with 4-methoxybenzylamine in the presence of EDCI and HOBt provided amide 2 in 71% yield. It was found that coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) was preferable over dicyclohexylcarbodiimide (DCC), due to the difficulty in.