Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of Ageladine A Analogs

Abstract

Regular ArticleAgeladine A (1), which is a pyrrol-2-aminoimidazole alkaloid isolated from the marine sponge Agelas nakamurai by Fusetani and colleagues 3) inhibits various subtypes of matrix metalloproteinases (MMPs) such as MMP-1, 2, 8, 9, 12, and 13. Among these MMPs, MMP-12 is considered to be associated with inflammatory diseases caused by macrophage infiltration such as skin diseases, 4-6) atherosclerosis, 7) aneurysms, 8) and cancers. 9-11) We had been studying the possibility of using MMP-12 inhibitors against inflammatory diseases, but had not been able to find a lead compound. Accordingly, we embarked on evaluating 1 as a new lead compound for novel MMP-12 inhibitors. Three total syntheses of 1 have been reported by Meketa and Weinreb 12,13) and Shengule and Karuso. 14) Recently, we also completed the total synthesis of 1 based on the biosynthetic route proposed by Fusetani et al., as shown in Chart 1. 1,15) While our synthetic route is almost the same as that independently reported by Shengule and Karuso,14) it is anticipated to be more efficient and practical when taking into account the reagents and chemical yields for each step. We wish to report here the structure-activity relationships for MMP-12 inhibitory activity performed by using the 37 ageladine A analogs prepared by featuring our synthetic route established for 1. 15) Results and Discussion MMP-12 Inhibitory Activity of Ageladine A Analogs We first, attempted to clarify the structural features of ageladine A (1) itself required for its MMP-12 inhibitory activity, and synthesized the 8 analogs 2-9. The MMP-12 inhibition assay was performed as per the manufacturer's (BioMol) protocol. The results of the MMP-12 inhibitory activity assay of these analogs are summarized in Table 1. The activity of two debromo-analogs 2 and 3 was found to disappear. The Nmethylpyrrole analog 4 showed no activity at all. In addition, the 4 analogs, 5-8 in which the amino or imino groups of imidazo[4,5-c]pyridine ring system are methylated and the deamino analog 9 showed weak or no activity. From these results, it was supposed that the two bromine atoms and the three NH groups (1-NH, 14-NH, and 15-NH 2 : ageladine A numbering) of 1 play an important role in its MMP-12 inhibitory activity. We paid particular attention to the influence of the bromine atoms, and anticipated that a slight Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of Ageladine A Analogs 1,2)Naoki ANDO* ,a and Shiro TERASHIMA b a Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.; 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan: and b Sagami Chemical Research Institute; 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan. Received November 16, 2010 accepted February 12, 2011 Synthesis of the 37 ageladine A analogs was accomplished by employing the total synthetic route of natural ageladine A previously explored by us. From the matrix metalloproteinase-12 (MMP-12) inhibitory activity assay carried out using the novel analogs, it appeared evident that t...

The Alkaloid Ageladine A, Originally Isolated from Marine Sponges, Used for pH-Sensitive Imaging of Transparent Marine Animals

“…The first source of Ageladine A was the marine sponge Agelas nakamurai and later it was isolated also from the sponge Agelas wiedenmayeri [3]. Methods for synthesizing Ageladine A were published in 2006 [4,5] and improved in the following years [6,7]. Some of its derivates showed increased matrix metalloproteinases inhibition [6,8,9].…”

One‐Pot Evolution of Ageladine A through a Bio‐Inspired Cascade towards Selective Modulators of Neuronal Differentiation

“…In the structural modification of ageladine A, the general focus has thus far been placed on easy synthetical replacements of the C4‐dibromopyrrole moiety with other heterocycles, and the substituent effects at the N1‐position have not been evaluated except for a simple methyl group . On the other hand, our new route to N1‐substituted ageladine A derivatives is inspired by a rather rare but naturally occurring PTM modification of arginine by lipid metabolites, discovered by Blair and coworkers in 2003 (Figure a) …”

“…In the structural modification of ageladine A, the general focus has thus far been placed on easy synthetical replacements of the C4-dibromopyrrole moiety with other heterocycles, [18,[24][25][26][27][28][29][30][31][32][33][34] and the substituent effects at the N1-position have not been evaluated except for as imple methyl group. [28,31] On the other hand, our new route to N1-substituted ageladine Ad erivatives is inspired by ar ather rare but naturally occurring PTM modification of arginineb yl ipid metabolites, discovered by Blair and coworkers in 2003 (Figure 2a). [35] Thus, the guanidine moiety of the arginineside chain in proteins can react under certain physiological conditions with the a,b-unsaturated aldehyde group of the lipid-oxidized metabolite 4-oxo-2(E)-nonenal( 4), efficientlyp roducing the C5-and N1-disubstituted 2-aminoimidazole 5,w hich mayb ecome the key intermediate of the N1-substituted ageladine A( see structure 11 in Figure 2b).…”

“…After the first total synthesis of ageladine A by Weinreb and coworkers, a number of total syntheses and derivatizations have been reported as part of detailed SAR studies . Of particular note, the groups of Karuso and Terashima utilized the Pictet–Spengler reaction of 2‐aminoimidazoles with various aldehydes followed by an oxidation (Figure ); these methods are applicable to the C4‐substituted ageladine A, but not to derivatives substituted at other positions such as N1.…”

“…[22,23] After the first totals ynthesiso fa geladine Ab yW einreb and coworkers, [24] an umber of total syntheses and derivatizations have been reported as part of detailed SAR studies. [18,[24][25][26][27][28][29][30][31][32][33][34] Of particularn ote, the groups of Karuso and Te rashimau tilized the Pictet-Spengler reaction of 2-aminoimidazoles with various aldehydes followed by an oxidation (Figure 1); [18,28] thesemethods are applicable to the C4-substituted ageladineA,b ut not to derivatives substituted at other positions such as N1. We wish to reportt he de novo synthesis of an ew class of ageladine Aa nalogues, especially focusing on the N1-substitution of ageladine A, whiche mployed ab io-inspired cascade in an one-pot procedure using easily availables tartingm aterials ( Figure 1).…”