487060-72-0Relevant academic research and scientific papers
Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin
Hawkins, Paige M. E.,Tran, Wendy,Nagalingam, Gayathri,Cheung, Chen-Yi,Giltrap, Andrew M.,Cook, Gregory M.,Britton, Warwick J.,Payne, Richard J.
, p. 15200 - 15205 (2020/10/23)
The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and a bulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days.
Total Synthesis of Ecumicin
Hawkins, Paige M. E.,Giltrap, Andrew M.,Nagalingam, Gayathri,Britton, Warwick J.,Payne, Richard J.
, p. 1019 - 1022 (2018/02/23)
The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM).
Synthetic Studies Toward the Skyllamycins: Total Synthesis and Generation of Simplified Analogues
Giltrap, Andrew M.,Haeckl, F. P. Jake,Kurita, Kenji L.,Linington, Roger G.,Payne, Richard J.
, p. 7250 - 7270 (2018/06/01)
Herein, we report our synthetic studies toward the skyllamycins, a highly modified class of nonribosomal peptide natural products which contain a number of interesting structural features, including the extremely rare α-OH-glycine residue. Before embarking on the synthesis of the natural products, we prepared four structurally simpler analogues. Access to both the analogues and the natural products first required the synthesis of a number of nonproteinogenic amino acids, including three β-OH amino acids that were accessed from the convenient chiral precursor Garner's aldehyde. Following the preparation of the suitably protected nonproteinogenic amino acids, the skyllamycin analogues were assembled using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. To access the natural products (skyllamycins A-C) the synthetic route used for the analogues was modified. Specifically, linear peptide precursors containing a C-terminal amide were synthesized via solid-phase peptide synthesis. After cleavage from the resin the N-terminal serine residue was oxidatively cleaved to a glyoxyamide moiety. The target natural products, skyllamycins A-C, were successfully prepared via a final step cyclization with concomitant formation of the unusual α-OH-glycine residue. Purification and spectroscopic comparison to the authentic isolated material confirmed the identity of the synthetic natural products.
Fmoc-OPhth, the reagent of Fmoc protection
Yoshino, Ryo,Tokairin, Yoshinori,Kikuchi, Mari,Konno, Hiroyuki
supporting information, p. 1600 - 1603 (2017/04/03)
Fmoc-OSu has been widely used for Fmoc protection of amino groups, especially amino acids, in solid phase peptide synthesis. However, it has been recognized that Fmoc-βAla-OH is formed as a by-product via the Lossen rearrangement during the reaction. Since we reconfirmed the formation of Fmoc-βAla-OH during the preparation of Fmoc-AA-OH by Fmoc-OSu, Fmoc-OPhth was designed and synthesized as a new Fmoc reagent to avoid the formation of Fmoc-βAla-OH. Furthermore, Fmoc protection by Fmoc-OPhth and Fmoc-SPPS were evaluated. The various Fmoc-amino acids prepared by Fmoc-OPhth were carried out in good yields and these are applicable in Fmoc-SPPS.
Total Synthesis of Skyllamycins A–C
Giltrap, Andrew M.,Haeckl, F. P. Jake,Kurita, Kenji L.,Linington, Roger G.,Payne, Richard J.
, p. 15046 - 15049 (2017/10/31)
The skyllamycins are a family of highly functionalized non-ribosomal cyclic depsipeptide natural products which contain the extremely rare α-OH-glycine functionality. Herein the first total synthesis of skyllamycins A–C is reported, together with the biofilm inhibitory activity of the natural products. Linear peptide precursors for each natural product were prepared through an efficient solid-phase route incorporating a number of synthetic modified amino acids. A novel macrocyclization step between a C-terminal amide and an N-terminal glyoxylamide moiety served as a key transformation to install the unique α-OH-glycine unit and generate the natural products in the final step of the synthesis.
Gymnangiamide, a Cytotoxic Pentapeptide from the Marine Hydroid Gymnangium regae
Milanowski, Dennis J.,Gustafson, Kirk R.,Rashid, Mohammad A.,Pannell, Lewis K.,McMahon, James B.,Boyd, Michael R.
, p. 3036 - 3042 (2007/10/03)
A cytotoxic aqueous extract from the marine hydroid Gymnangium regae provided a novel linear pentapeptide, designated gymnangiamide (1). The planar structure of 1 was elucidated by interpretation of spectral data as well as chemical degradation and derivatization studies. In addition to the amino acids isoleucine and phenylserine, this peptide contained N-desmethyldolaisoleuine, O-desmethyldolaproine, and α-guanidino serine, three residues that have not previously been reported in a natural product. The absolute configurations of the constituent amino/guanidino acids were determined by chemical degradation and derivatization, followed by HPLC and LC-MS comparison with authentic standards. Gymnangiamide (1) was moderately cytotoxic against a number of human tumor cell lines in vitro.
Peptide inhibitors of CDK2-cyclin A that target the cyclin recruitment-Site: Structural variants of the C-Terminal Phe
Atkinson, Gail E.,Cowan, Angela,McInnes, Campbell,Zheleva, Daniella I.,Fischer, Peter M.,Chan, Weng C.
, p. 2501 - 2505 (2007/10/03)
A focused series of octapeptides based on the lead compound H-His-Ala-Lys-Arg-Arg-Leu-Ile-Phe-NH2 1, in which the C-terminal phenylalanine residue was replaced by α and/or β-modified variants, was synthesized using solid-phase chemistry. Both the L-threo-β-hydroxy-phenylalanine (β-phenylserine, Pse) and (2S)-phenylalaninol derivatives, as competitive binders at the cyclin-recruitment site, displayed potent inhibitory activity towards the CDK2-cyclin A complex. Unexpectedly, the D-threo-Pse derivatives also showed inhibitory activity.
Monitoring the solid phase synthesis of analogues of lysobactin and the katanosins using in situ MALDI-TOF MS
Egner, Bryan J.,Bradley, Mark
, p. 14021 - 14030 (2007/10/03)
A method of solid phase reaction analysis is described using an in situ cleavage process (TFA vapour) followed by MALDI-TOF MS analysis. The process is demonstrated by the solid phase synthesis of a depsipeptide based on the antibiotic Lysobactin.
