61125-52-8Relevant articles and documents
Diketopiperazines as a tool for the study of transport across the Blood-Brain Barrier (BBB) and their potential use as BBB-shuttles
Teixido, Meritxell,Zurita, Esther,Malakoutikhah, Morteza,Tarrago, Teresa,Giralt, Ernest
, p. 11802 - 11813 (2007)
Here we prepared and evaluated two libraries of mono-N-methylated and di-N-methylated diketopiperazines (DKPs) by parallel artificial membrane permeability assay and immobilized artificial membrane chromatography in order to obtain information on the features that govern the passage of peptidic molecules across the blood-brain barrier (BBB) by passive diffusion. On the basis of the results from these two libraries, we prepared and evaluated several DKP-baicalin and DKP-dopamine constructs. The DKPs or cyclic dipeptide scaffolds can be considered a novel family of brain delivery systems (BBB-shuttles) to transport to the brain drugs and other cargos that cannot cross the BBB unaided.
A tRNA-dependent two-enzyme pathway for the generation of singly and doubly methylated ditryptophan 2,5-diketopiperazines
Giessen, Tobias W.,Von Tesmar, Alexander M.,Marahiel, Mohamed A.
, p. 4274 - 4283 (2013/07/26)
A large number of bioactive natural products containing a 2,5-diketopiperazine (DKP) moiety have been isolated from various microbial sources. Especially tryptophan-containing cyclic dipeptides (CDPs) show great structural and functional diversity, while little is known about their biosynthetic pathways. Here, we describe the bioinformatic analysis of a cyclodipeptide synthase (CDPS)-containing gene cluster from Actinosynnema mirum spanning 2.9 kb that contains two putative DKP-modifying enzymes. We establish the biosynthetic pathway leading to two methylated ditryptophan CDPs through in vivo and in vitro analyses. Our studies identify the first CDPS (Amir-4627) that shows high substrate specificity synthesizing only one main product, cyclo(Trp-Trp) (cWW). It is the first member of the CDPS family that can form ditryptophan DKPs and the first prokaryotic CDPS whose main product constituents differ from the four amino acids (Phe, Leu, Tyr, and Met) usually found in CDPS-dependent CDPs. We show that after cWW formation a S-adenosyl-l-methionine- dependent N-methyltransferase (Amir-4628) conducts two successive methylations at the DKP-ring nitrogens and additionally show that it is able to methylate four other phenylalanine-containing CDPs. This makes Amir-4628 the first identified DKP-ring-modifying methyltransferase. The large number of known modifying enzymes of bacterial and fungal origin known to act upon Trp-containing DKPs makes the identification of a potent catalyst for cWW formation, encoded by a small gene, valuable for combinatorial in vivo as well as chemoenzymatic approaches, with the aim of generating derivatives of known CDP natural products or entirely new chemical entities with potentially improved or new biological activities.
Synthesis of a reported calpain inhibitor isolated from Streptomyces griseus
Donkor,Sanders, M. Lee
, p. 2647 - 2649 (2007/10/03)
The reported diketopiperazine calpain inhibitor, cis-L-L-3,6-bis-(4-hydroxybenzyl)-1,4-dimethylpiperazine-2,5-dione 1, and its analogues 3 and 4 were synthesized from the corresponding amino acids. The previously assigned structure of 1 is confirmed but n
