18226-11-4Relevant articles and documents
MACROCYCLIC AMIDES ACTING AS PLASMEPSIN INHBITORS FOR THE TREATMENT OF MALARIA
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Paragraph 076-077; 078, (2021/06/26)
The present invention relates to medicine and in particular to the treatment of malarial infections, more particularly to inhibitors of malarial aspartic proteases - plasmepsins. Even more particularly, the invention relates to macrocyclic amides and pharmaceutical compositions thereof and their use as inhibitors for plasmepsins (Plm).
Improved Strategy for the Synthesis of the Anticancer Agent Culicinin D
Stach, Michaela,Weidkamp, Andreas J.,Yang, Sung-Hyun,Hung, Kuo-Yuan,Furkert, Daniel P.,Harris, Paul W. R.,Smaill, Jeff B.,Patterson, Adam V.,Brimble, Margaret A.
, p. 6341 - 6350 (2015/10/06)
The anticancer peptaibol culicinin D was synthesised via a newly developed pathway. This route included an improved attachment of a C-terminal amino acid alcohol building block to 2-chlorotrityl chloride resin. A model system utilising readily available Fmoc-alaninol as the substitute for the unusual APAE building block was developed to investigate the resin-loading by N-anchoring of the first C-terminal residue and an intramolecular O-N acyl shift. The use of both Fmoc SPPS and the crucial O-N acyl transfer afforded a C-terminal alcohol that enabled the synthesis of a library of five related peptaibols. This model system was then applied to the synthesis of culicinin D. The C-terminal APAE building block was anchored to 2-chlorotrityl chloride resin in 67 % loading yield using the optimised conditions, and culicinin D (6.31 mg, 4 %) was prepared by SPPS prior to peptide cleavage and O-N acyl shift. This synthetic strategy was also used to prepare a diastereomer of culicinin D containing the unnatural (S)-AHMOD amino acid. The anticancer agent Culicinin D, active against breast tumor cells, was synthesised on the solid phase. The resin loading was improved by attachment of first residue to solid-phase via the amine rather than the alcohol. After SPPS and cleavage, the peptide alcohol was formed via an intramolecular O-N transfer reaction. Successful synthesis of several culicinin D analogues demonstrated the feasibility of this new synthetic strategy.
A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds
James, Thomas,Maclellan, Paul,Burslem, George M.,Simpson, Iain,Grant, J. Andrew,Warriner, Stuart,Sridharan, Visuvanathar,Nelson, Adam
supporting information, p. 2584 - 2591 (2014/04/17)
Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections. This journal is the Partner Organisations 2014.