Structural Diversity using Hyp “Customizable Units”: Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides

Abstract

The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery.

Structural diversity using amino acid “Customizable Units”: conversion of hydroxyproline (Hyp) into nitrogen heterocycles

“…Moreover, the structural diversity would be expanded by elimination of the 4-hydroxy group, to give 2-alkyl-2,5-dihydro-1H-pyrroles, which can be readily converted into iminosugar and alkaloid analogues 5 (Jin et al 2009 ; Blunt et al 2009 ; Butler et al 2008 ; Boto et al 2009 ). As reported before, structural diversity could be translated into biological diversity (Cuevas et al 2021 ; Pavlinov et al 2019 ; Galloway et al 2014 ).…”

“…Different customizable units such as glycine, serine, threonine, glutamic acid, proline or hydroxyproline have been described (Boto et al 2021 ). We have introduced 4-hydroxyproline as a versatile building block for the production of unusual amino acids (Romero-Estudillo et al 2015 ; Cuevas et al 2021 ), including N -alkyl derivatives (Saavedra et al 2019 , 2020 ), and reported its use as a “doubly customizable unit” (Hernández et al 2021 ), as shown in Scheme 1 . In a first step, the substrates 1 underwent a decarboxylation-alkylation reaction to afford 2-alkyl pyrrolidines 2 with high stereoselectivity.…”

Site-selective modification of peptide backbones

“…11,50b Other applications of this methodology have allowed the preparation of diketopiperazine scaffolds with four different substituents, 51 and the production of a library of cyclic antitumoral peptides, as sansalvamide A analogues. 52 Recently the use of Hyp as a doubly customizable unit was reported by the same group (Scheme 17). 11 A one-pot radical decarboxylation-oxidation-addition of C-nucleophiles allowed the modification of the C-terminal position of the peptide 67 and replacement of the carboxyl group by a variety of other chains, with high stereoselectivity due to the presence of an stereogenic center at C-4.…”

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

“…Our group and others have described different applications of the β-scission of O -radicals, generated from alcohols, acetals or acids under Suárez conditions, to the preparation of bioactive products or their analogs ( Saavedra et al, 2020 ; Cuevas et al, 2021 and references cited therein). However, in these protocols a further development was introduced: coupling these oxidative scission processes to the addition of carbon, nitrogen, phosphorous, oxygen, hydrogen, sulfur and other nucleophiles ( Boto, Gallardo et al, 2006 ; 2007a ; Boto, Hernández et al, 2008a,b ; 2009 ; Batchu et al, 2014 ; Carro et al, 2017 ; Saavedra et al, 2018 ; Santana and González, 2020 ).…”