A convergent approach using two key intermediates, segment A [a
l-proline-l-α-hydroxy-β-homoarginine-d-phenylalanine (Pro-hArg-d-Phe)
tripeptide] and segment B [a vinylogous
l-tyrosine-l-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was
developed for the synthesis of cyclotheonamide B (Scheme ). The starting compound for the preparation of
the hArg moiety 7, the
predominant part of segment A, was
N
α-(benzyloxycarbonyl)-N
ω,N
ω‘-bis(tert-butyloxycarbonyl)-l-arginine methyl ester (15, Scheme 2), which was converted
into the aldehyde 16 and subsequently
homologated using [tris(methylthio)methyl]lithium as a
carboxylic acid anion equivalent. Coupling
with properly protected Pro and d-Phe derivatives gave
smoothly the desired Pro-hArg-d-Phe
tripeptide derivative 24. The key feature of segment B,
i.e., the l-tyrosine-derived
α,β-unsaturated
γ-amino acid 4, was prepared by a Wadsworth−Emmons
olefination of the aldehyde 29 (Scheme 3)
derived from N-(tert-butyloxycarbonyl),
O-tert-butyl-l-tyrosine methyl ester
(28). Selective
N-(tert-butyloxycarbonyl) removal in the presence of the aryl
tert-butyl ether present in the fully protected
segment B, i.e.,
32, was achieved by treatment
with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield.
Coupling of the key intermediates 24 and
34
using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) afforded the
protected linear pentapeptide 35 in high yield (Scheme 4).
Treatment of 35 with
Pd(PPh3)4/morpholine resulted in simultaneous removal of the C-terminal
allyl group and the N-terminal
allyloxycarbonyl group to yield 36. Ring closure was
effected under dilution conditions by treatment
with TBTU/1-hydroxybenzotriazole/4-(dimethylamino)pyridine and
gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl
group with Dess−Martin periodinane (24 h, 40
°C) in the presence of tert-butyl alcohol gave
38, which was then subjected to
O,N-deprotection
with trifluoroacetic acid/thioanisole. Subsequent HPLC
purification afforded cyclotheonamide B
in an overall yield of 1.8% in 17 steps.
A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentration of 40 microM all compounds appeared to be very active against Mycoplasma gallisepticum K154. The most active compounds were found in the amide series and show growth inhibition in the nanomolar range. These compounds are 4 times more active than tylosin, a macrolide antibiotic, which is used therapeutically in veterinary practice. In the presence of copper, amides derived from 3 are more active than corresponding amidines. Increased activity following derivatization of 3 may be due to the presence of a third coordination site for copper in the title compounds. Evaluation of biological data revealed that antimycoplasmal activity of amides derived from 3 is dependent on lipophilicity. For these amides a good linear correlation was found between antimycoplasmal activity and hydrophobic fragmental values for substituents considered. This quantitative structure-activity relationship study indicated that antimycoplasmal activity was increased upon a decrease of these hydrophobic fragmental values.
[formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.
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