Synthesis of barbiturate-based methionine aminopeptidase-1 inhibitors

Abstract

The syntheses of a new class of barbiturate-based inhibitors for human and E. Coli Methionine Aminopeptidase -1 (MetAP-1) are described. Some of the synthesized inhibitors show selective inhibition of the human enzyme with high potency. KeywordsType-1 MetAP inhibitors; barbiturates Cellular protein synthesis starts with an N-terminal methionine in the eukaryotic cells or with a formylmethionine in the prokaryotic cells. Removal of the methionine residue is essential for proper folding, post-translational modifications and translocation of the synthesized proteins. 1 The metalloenzymes methionine aminopeptidases (MetAPs) catalyze the hydrolytic removal of the N-terminal methionine residue from the newly synthesized proteins. 1 While the prokaryotic cells contain only the type-1 enzyme, eukaryotic cells contain both the type-1 and -2 enzymes in the cytosol. 2 Deletion of the MetAP is shown to be lethal in various bacteria. 2Since the discovery that the irreversible MetAP-2 inhibitor fumagillin prevents angiogenesis, both reversible and irreversible inhibitors for this enzyme have been extensively studied as potential anti-angiogenesis and anti-cancer agents. 3 Selective inhibition of MetAP-1 in bacteria (or in parasites) over the human enzymes has been shown to be a promising approach in designing new antibacterial 4 and antimalarial 5 agents. The role of MetAP-1 in human cell cycle progression has been elucidated recently. 6 Selective inhibition of the human MetAP-1 (over MetAP-2) led to the arrest of cell division and induction of apoptosis in leukemia cells. 6In contrast to MetAP-2, there are only a few reports in the literature on inhibition of human MetAP-1. Peptide hydroxamic acids are reported to be competitive inhibitors for human MetAP-1 with moderate potency. 7 Substituted pyridines were identified as another class of human MetAP-1 inhibitors using high-throughput screening of 175,000 small organic molecules. 3b Ovalicin, the highly-potent, non-competitive, natural product inhibitor for *Corresponding authors. Tel: +1 701 231 7888; fax: +1 701 231 8331; e-mail addresses: sanku.mallik@ndsu.edu; dk.srivastava@ndsu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Under physiological conditions, the metal ions in the active site of MetAPs are not firmly established. The active site binds to two divalent transition metal ions and the residues responsible for binding to the metal ions are conserved. 4 One of these two bound metal ions undergoes a rapid exchange with free metal ions in solution. 4 Since Co (II) ions activate all MetAPs, usually the inhibitors...

1, 4-Addition of Terminal Alkynes to Conjugated Enones in Water Using Green Catalyst Bis[(l)prolinato-N,O]Zn—An Environmentally Benign Protocol

“…The chalcone was prepared according to the literature procedure [38,39]. All reactions and purity of terminal alkynes and enones were monitored by thin layer chromatography (TLC) using aluminium plates coated with silica gel (Merck) employing ethylacetate and hexane (3:7).…”

Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants

“…[9][10][11][12] Benzylidenebarbiturates are employed in several well known reactions in the literature 10,[13][14][15][16][17] and have even been used as methionine aminopeptidase inhibitors. 18 The preparation of the 5-chloro-5-benzolbarbiturates was Vol. 22, No.…”

Advances in Bacterial Methionine Aminopeptidase Inhibition

“…In addition to the classes of bacterial MetAP inhibitors discussed, other classes of inhibitors have been identified, such as barbiturates [66], salicylate derivatives [33,67], catechols [43,64,65,68] and bengamide derivatives [69]. In general, the barbiturate based inhibitors exhibit moderate activity against Ec MetAP1 (K i = 4 – 517 μM, Co(II) cofactors) [66], with only one compound exhibiting potent activity (K i = 0.05 μM) and were found to be nonselective inhibitors of MetAPs, as demonstrated by comparable activity with Hs MetAP1.…”

“…In general, the barbiturate based inhibitors exhibit moderate activity against Ec MetAP1 (K i = 4 – 517 μM, Co(II) cofactors) [66], with only one compound exhibiting potent activity (K i = 0.05 μM) and were found to be nonselective inhibitors of MetAPs, as demonstrated by comparable activity with Hs MetAP1. Because the compounds are not very active against MetAPs, exhibit nonselective inhibition and only one report exists detailing their activity, we have chosen to exclude a detailed overview.…”