- NOVEL COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (formula 1) wherein R1,R2, R3, R4, R5, X, m and n are defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.
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- Design and synthesis of all diastereomers of cyclic pseudo-dipeptides as mimics of cyclic CXCR4 pentapeptide antagonists
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The four diastereomers of 2,5-bis[(3-guanidino)propyl]-1-[3-(4- hydroxyphenyl)propionyl]-7-(2-naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (54-57) and of 2,5-bis[(3-guanidino)propyl]-1-(4-hydroxyphenylacetyl)-7-(2- naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (58-61) were synthesized by a divergent methodology from l- and d-glutamic acids. The 11-membered ring core was made by ring closing metathesis of linear bis(allylamines), and the guanidyl functions were introduced by a simultaneous double Mitsunobu reaction using bis(Boc)guanidine. These compounds were designed to mimic cyclic pentapeptide FC131 (c[Gly-d-Tyr-Arg-Arg-Nal]). The Royal Society of Chemistry.
- Cluzeau, Jerome,Oishi, Shinya,Ohno, Hiroaki,Wang, Zixuan,Evans, Barry,Peiper, Stephen C.,Fujii, Nobutaka
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p. 1915 - 1923
(2008/02/10)
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- Enantioselective synthesis of the protein phosphatase inhibitor (-)-motuporin
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A highly convergent asymmetric synthesis of the protein phosphatase inhibitor motuporin 1a is described. Synthesis and coupling of the individual peptide fragments [34 + -35 → 51] followed by macrocyclization afforded the fully protected motuporin precursor 33, which is converted to the natural product by dehydration and ester hydrolysis, Six of the eight stereogenic centers associated with the natural product were introduced using asymmetric crotylsilane bond construction methodology. Our approach features an efficient Pd(0)-catalyzed cross-coupling reaction between a configurationally well-defined vinyl zinc intermediate 22 and an (E)-vinyl iodide 7, which afforded compound 43, resulting in the construction of the trisubstituted (E,E)-diene system of the motuporin side chain. Improved reaction conditions for macrocyclization in the formation of 33 are also detailed.
- Hu, Tao,Panek, James S.
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p. 11368 - 11378
(2007/10/03)
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- Design and preparation of serine-threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 1. Evaluation of key inhibitory features and synthesis of a rationally stripped-down nodularin macrocycle
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The natural nodularin and microcystin toxins are powerful but non-selective inhibitors of the ubiquitous and structurally related eukaryotic Ser-Thr protein phosphatases, PP1 and PP2A, enzymes that are intimately involved in controlling cellular metabolism. Both families of toxin are cyclic tri-isopeptides typified by the presence of two free carboxylic acid groups, a dehydroamino acid moiety, and a large, rigid exocyclic lipophilic side-chain. To learn how to design specific inhibitors for each enzyme, the nature of specific interactions with potential inhibitor-conferring moieties in the toxin was considered. Borohydride reduction of the dehydroalanine residue present in microcystin-LR, a potential Michael acceptor, gave two diastereoisomeric dihydromicrocystin products. Each of these displayed subnanomolar activities as inhibitors for PP2A, as for the parent compound, indicating that the dehydroamino acid residue in microcystin and, probably, in nodularin, is not essential for activity. Other conserved features appeared to be required to confer activity, hence strategies towards the synthesis of simplified non-dehydroamino acid-containing analogues of each macrocycle type were considered. In each case it was planned to elaborate the lipophilic side-chain functionality after the formation of the macrocyclic ring. In order to synthesize the precursor nodularin-type macrolactam, two peptide-bond disconnections of the ring were investigated using a model system, cyclo-[β-Ala-(R)-Glu-α-OMe-γ-Sar-(R)-Asp-α-OMe-β-(S) -Phe-], one bond disconnecting between the sarcosine carboxy group and the (2R)-Asp N-atom and the other disconnecting between the (2R)-Asp β-carboxy group and the (2S)-PhC N-atom. Preparation of the linear precursors was achieved using solution-phase chemistry without incident. Macrolactamisation via the displacement of the β-pentafluorophenyl ester of the (2R)-Asp α-methyl ester residue by the free amino group of the (2S)-phenylalanine residue proceeded in excellent yield (89%), but the alternative strategy failed. Application of the successful macrolactamisation strategy to other nodularin macrocycles and to the construction of the microcystin-type macrocycle is described in the following article.
- Mehrotra, Amit P.,Webster, Kerri L.,Gani, David
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p. 2495 - 2511
(2007/10/03)
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- Synthesis of functionalised cyclic pentapeptide analogues of the serine-threonine protein phosphatase inhibitor nodularin
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A generic synthesis of cyclic peptidic analogues of nodularin incorporating suitable functionality for synthetic elaboration is described, providing access to new protein phosphatase inhibitors.
- Mehrotra, Amit P.,Gani, David
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p. 6915 - 6918
(2007/10/03)
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- Synthesis of a Novel Class of Peptides: Dilactam-Bridged Tetrapeptides
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As model compounds for the study of constrained peptides, the following lactam-bridged derivatives were synthesized: Ac-L--D--NHMe (I), Ac-L--L--NHMe (II), Ac-L--NHMe (III), Ac-L--D--NHMe (IV), Ac-L--L--NHMe (V), and Ac-L--NHMe (VI).Benzyloxycarbonyl and tert-butyloxycarbonyl groups were employed for amine protection and the benzyl and methyl esters for carboxyl protection.Coupling reactions were carried out by the use of active esters or through azide activation.Cyclization reactions were carried out by adding the active ester hydrochlorides into large volumes of pyridine at elevated temperatures.The cyclic intermediates were obtained in yields of 45-50percent.Fragment condensation of the cyclic dipeptides yielded the corresponding dilactam-bridged tetrapeptides.
- Manesis, Nick J.,Goodman, Murray
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p. 5331 - 5341
(2007/10/02)
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