Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1 ) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly 6 ]- 1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly 6 ]- 1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64 Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11 C-labeled Pittsburgh compound-B ( 11 C-PIB), which binds specifically fibrillar Aβ plaques, 64 Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood–brain barrier (BBB), peptide 1 and [azaGly 6 ]- 1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans , and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.

6-Hydroxymethyl indolizidin-2-one amino acids were synthesized in 10 steps from l-serine by intramolecular ring opening of a symmetrical epoxide and lactam formation. X-ray analyses indicated the bicycles replicated ideal peptide type II′ β-turn central dihedral angle geometry. Inside a prostaglandin-F2α receptor modulator, the 6-hydroxymethyl analogue retained inhibitory activity on myometrial contractility.

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆4-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆4-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.

Enantiomerically pure 4-vinylproline (Vyp) was synthesized by a five-step approach from N-(Boc)­iodo-alanine (2) featuring copper-catalyzed SN2′ substitution of the corresponding zincate onto (Z)-1,4-dichlorobut-2-ene to prepare methyl 2-N-(Boc)­amino-4-(chloromethyl)­hexenoate (3). Intra- and intermolecular displacement of the chloride provided respectively Vyp and methyl 2-N-(Boc)­amino-4-(azidomethyl)­hexenoate (7) suitable for the synthesis of constrained peptide analogs.

Conformationally rigid α‐amino‐δ‐lactam surrogates of Glu‐Gly and Gln‐Gly dipeptides have been synthesized from α‐amino‐γ‐vinyl‐δ‐lactam precursors. A reductive cyclization protocol from the respective (4R)‐ and (4S)‐2‐N‐(Boc)amino‐4‐(azidomethyl)hexenoates gave δ‐lactams, which were converted to the corresponding dipeptide surrogates by N‐alkylation with methyl bromoacetate. The utility of these α‐amino‐γ‐vinyl‐δ‐lactam building blocks was demonstrated by olefin oxidation and peptide coupling to prepare constrained Glu and Gln residues.