Arnaud Salaün

Z/E isomerism in Nα-Nα-disubstituted hydrazides and the amidoxy bond: application to the conformational analysis of pseudopeptides built of hydrazinoacids and α-aminoxyacids.

We have investigated the Z/E isomerism of the hydrazide link (CO-NH-N) and amidoxy link (CO-NH-O). The study was first focused on small molecular models using NMR and X-ray diffraction. It allowed determination of simple NMR criterions to differentiate easily the Z and E forms, which were then applied to investigate the behavior of these links inside the corresponding oligomers. Our results concerning the hydrazide link corroborate pioneering work that had been done in the 1970s except in the case were it is located inside aza-β(3)-cyclopeptides, where the old empirical rules failed to predict the right geometry of the link. The geometrical preference of the amidoxy bond is also unambiguously established and differs clearly from recent theoretical calculations. Our findings help rationalize the close self-organization ability of aza-β(3)-peptides and α-aminoxypeptides, two recently described foldamers.

Aza-β3-cyclopeptides: A New Way of Controlling Nitrogen Chirality

Sixteen and 24 membered aza-beta(3)-peptidic macrocycles containing a alpha-hydrazinoacid or a beta(3)-aminoacid were synthesized. The conformation of these pseudopeptides was determined by using NH chemical shift analysis, NH extinction, VT-NMR experiments, and X-ray diffraction. The study shows that a stable conformation is retained between 223 and 413 K. The latter is characterized by an uninterrupted internal H-bond network and a syndiotactic arrangement of the asymmetric centers. It means that the presence of the optically pure residue acts as a conformational lock to select a single enantiomer through the cyclization by controlling the absolute configuration of all the nitrogen atoms. To our knowledge, this represents the first example of a dynamic enantioselection process involving several centers prone to pyramidal inversion. These results give a new impulsion to the control of nitrogen chirality, which remained limited to small cycles for 60 years.

Aza-beta3-cyclotetrapeptides.

The cyclization of aza-beta(3)-tetrapeptides gives access to new CTP (cyclotetrapeptide) analogues. These stereocontrolled templates are assembled without any asymmetric synthesis. X-ray crystallographic structure and NMR analysis show that the macrocyclic scaffold is characterized by a fully cooperative intramolecular H-bond network, in sharp contrast with the nanotubular assemblies observed for beta(3)-cyclotetrapeptides. This folding property reduces considerably the polarity of aza-beta(3)-tetrapeptides and should be useful in addressing intracellular targets.

Postsynthetic modification of C3-symmetric aza-beta3-cyclohexapeptides.

We have synthesized a series of C3-symmetric aza-beta3-cyclohexapeptides with functionally diverse side chains carrying a good functional diversity. The very simple chemical sequence that we used (debenzylation/acylation) makes it certain that the series synthesized could be easily expanded, leading to a wide family of C3-symmetric cyclohexapeptides analogues. The macrocyclic backbone of the aza-beta3-cyclohexapeptides shows a highly ordered conformation that is sustained by a dense intramolecular H-bond network where all endocyclic NHs are hydrogen bonded, the side chains being projected in equatorial position around the macrocycle. The resulting internal secondary structure relies on the cooperative alternation of two slightly different C8-bifidic pseudocycles, which differ mainly by the hybridization of the Nalpha nitrogen atom (N-Nsp3-turn and N-Nsp2-turn). In both cases, the nitrogen lone pair participates to stabilize the pseudocycle. This has been established by NMR experiments and X-ray diffraction analysis. As in the precursors, the nitrogen stereocenters are characterized by a strikingly slow rate of pyramidal inversion, considering the size of the macrocycle.

Novel Cyclopeptides for the Design of MMP Directed Delivery Devices: A Novel Smart Delivery Paradigm

ABSTRACTPurposeMatrix metalloproteinases (MMP) are a family of proteolytic enzymes, the expression of which in a key step of tumor progression has been better defined recently. The studies highlighted the ongoing need for very specific inhibitors, substrates or release devices designed to be selective for one or at least very few MMPs.MethodsThis report deals with the design, synthesis and in vitro evaluation of linear and especially novel cyclic peptidic moieties, embodying MMP cleavable sequences designed to answer these questions. FRET (fluorescence resonance energy transfer) labelling via chromophore-modified amino-acids was used to give access to enzyme kinetics.ResultsEvaluation of these peptides showed that cyclisation gives rise to high specificity for certain MMP, suggesting that this approach could provide very specific MMP substrate. Moreover, cyclic structures present a very good plasma stability.ConclusionsThese original derivatives could allow the design of MMP-controlled delivery devices, the specificity of which will be retained in complex biological media and in vivo.

Stereodynamics of nitrogen chiral centers in aza-β3-cyclodipeptides.

The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza-β(3)-cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight-membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X-ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations. The relative configuration associated with ring chirality and with the two nitrogen chiral centers is governed by steric crowding and adopts the (P)S(N) S(N)/(M)R(N)R(N) combination which projects side chains in equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is correlated with the ring reversal. The process is significantly hindered as was shown by VT-NMR experiments run in C2D2Cl4, which did not make it possible to determine the barrier to inversion. Finally, these findings make it conceivable to resolve enantiomers of aza-β(3)-cyclodipeptides by modulating the backbone decoration appropriately.