Catechoyl-Dipeptides as Leucine Aminopeptidase Inhibitors

Compounds consisting of the catechol group con­ nected to an amino acid or a small peptide only re­ cently have been the subject of few papers concern­ ing their structure-activity relationship. A number of 2,3-dihydroxybenzoic acid amides such as polyamine derivatives: parabactin [1 ], agrobactin [2], vibriobactin [3], or amino acid derivatives: glycine [4], lysine [5], serine [6 ], and threonine [7], as well as depsipeptide enterobactin [8 ] have been iso­ lated from bacterial cultures. Due to the powerful ligand potency of catechol groups most of them act as iron carriers of natural origin — siderophores [9]. However, only two 2,3-dihydroxybenzoyl dipep­ tides: A la—Thr [10] and A la—(N~ — A c—N~ — OH)Orn [11] have been isolated from microbial fer­ mentation products. They exhibited inhibitory properties against therapeutically important en­ zymes: leucine aminopeptidase [EC 3.4.11.1] [10] and thymidylate synthase [EC 2.1.1.45] [12] respec­ tively. A variety of redox-active agents, including catechols, exhibit antitumor activity in vitro as well as in vivo [13]. The compounds with 3,4-dihydroxyphenyl groups related to DOPA [14] play the key role among them. A paper reporting catechol-like compounds showing greater potency and selectivity against malignant melanoma than the natural prod­ uct, L-DOPA methyl ester, has been published re­ cently [15]. It also appeared that penicillin deriva­ tives having catechol moieties exhibit up to 30 to 60-