Natural products play an important role in the development of drugs, especially for the treatment of infections and cancer, as well as immunosuppressive compounds. However, the number of natural products is limited, whereas millions of hybrids as combinations of parts of different natural products can be prepared. This new approach seems to be very promising in the development of leads for both medicinal and agrochemical applications, as the biological activity of several new hybrids exceeds that of the parent compounds. The advantage of this concept over a combinatorial chemistry approach is the high diversity and the inherent biological activity of the hybrids.
Oligomers of a new class of sugar amino acids (SAA) using a xylofuranoic acid has been shown to generate a robust 14-helix. The design involved the use of xylofuranose with a cis arrangement between the amine and carboxyl groups to promote the adoption of a 14-helix instead of a mixed 12/10-helix observed in a sugar oligomer using a ribofuranoic acid and beta-Ala. The observation of a stable right-handed 14-helix in a cis-SAA is unprecedented.
The oligomers of constrained cis-exo-beta-norbornene amino acid were synthesised and characterised by extensive NMR, CD, IR and MD studies. The results showed the formation of both right and left handed consecutive 6-membered hydrogen-bonded strands for [2S,3R] and [2R,3S] enantiomers, respectively.
An enantioselective synthesis of natural anticancer macrolide pladienolide B is described. The synthetic highlights include Sharpless asymmetric epoxidation, ring closing metathesis (RCM), Ireland-Claisen rearrangement, Shi epoxidation, and Pd-catalyzed Stille coupling as key steps. The synthetic route also allowed the synthesis of the truncated analogues (41a-d) of pladienolide B.
Tendencies of forming stable helices of heterooligomers composed of alternating rigid cis-beta-sugar amino acid and flexible beta-hGly motifs have been investigated, using a combination of molecular mechanics, CD, FT-IR, and NMR techniques. The results show that the solution structures of these oligomers exist as robust right-handed 14-helices. Here, we examine the role of conformationally rigid cis-beta-sugar amino acid in preorganizing the conformation of beta-hGly to form the 14-helix. Our findings also show that a right-handed 14-helix can be formed with as few as four properly sequenced heterogeneous residues. These results represent the expansion of the conformational pool of sugar amino acid in the design of well-folded 14-helices, which can be used to develop beta-peptides endowed with biological activity.
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