Comparative effects of trifluoromethyl- and methyl-group substitutions in proline

Kubyshkin, Vladimir; Pridma, Stanislav O.; Budiša, Nediljko

doi:10.1039/c8nj02631a

Cited by 18 publications

(14 citation statements)

References 105 publications

(139 reference statements)

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“…The cis -diastereomer 1 with the C–F bond pointing in the same direction as the carboxymethyl group, appeared more polar compared to the trans -isomer 2 , where the direction was opposite (Δlog P cis/trans ≈ −0.18). The same effect was observed in 4-hydroxyprolines as well [ 13 ] (Δlog P cis/trans ≈ −0.19).…”

Section: Resultssupporting

confidence: 73%

“…There is a rich portfolio of fluorine-containing proline analogues that have been developed to date (Figure 1B): fluorinated [6][7][8][9][10][11][12], trifluoromethylated [13][14][15][16][17][18][19][20][21][22][23], chimeric [16,19,[24][25][26][27][28][29], conformationally restricted [30][31][32][33] having variations in the ring size [34][35][36][37][38][39], non-α [40][41][42][43][44], and other analogues [45][46][47][48]. The fluorine-containing functional groups are usually chemically inert under most biologically relevant conditions.…”

Section: Introductionmentioning

confidence: 99%

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Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

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Section: Resultssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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“…The emergence of fluorine in drug design highlighted the potential of fluorinated amino acids, peptides and mimetics, and the possibility to tailor their geometry with such a peculiar element . In particular, proline surrogates, which were fluorinated or trifluoromethylated in their lateral chain, were examined as useful conformational tuning tools that allowed fine control of the cis ‐ or trans ‐prolyl amide bond population . Previous studies on model peptides have established the stereoelectronic effects imparted by the CF 3 group on the rotational energy barrier and puckering of the oxazolidine core .…”

Section: Figurementioning

confidence: 99%

Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates

et al. 2019

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Proline is often found as a turn inducer in peptide or protein domains. Exploitation of its restricted conformational freedom led to the development of the d‐Pro‐l‐Pro (corresponding to (R)‐Pro–(S)‐Pro) segment as a “templating” unit, frequently used in the design of β‐hairpin peptidomimetics, in which conformational stability is, however, inherently linked to the cis–trans isomerization of the prolyl amide bonds. In this context, the stereoelectronic properties of the CF3 group can aid in conformational control. Herein, the impact of α‐trifluoromethylated proline analogues is examined for the design of enhanced β‐turn inducers. A theoretical conformational study permitted the dipeptide (R)‐Pro–(R)‐TfmOxa (TfmOxa: 2‐trifluoromethyloxazolidine‐2‐carboxylic acid) to be selected as a template with an increased trans–cis rotational energy barrier. NMR spectroscopic analysis of the Ac‐(R)‐Pro–(R)‐TfmOxa–(S)‐Val‐OtBu β‐turn model, obtained through an original synthetic pathway, validated the prevalence of a major trans–trans conformer and indicated the presence of an internal hydrogen bond. Altogether, it was shown that the (R)‐Pro–(R)‐TfmOxa template fulfilled all crucial β‐turn‐inducer criteria.

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“…At the same time, relatively hydrophobic prolyl residues form the exterior of the resulting triple helix. [2][3][4] Post-translational 5 or synthetic 6 hydroxylations of prolyl fragments partially restore the polarity of the collagen exterior, 7 although it is believed that the role of this modification is different for collagen stability. 8 The fact that the collagen helix formation is driven by polar interaction between backbone amides ("polar in") is rather peculiar since this assembly occurs in an aqueous medium, which is polar as well.…”

Section: Introductionmentioning

confidence: 99%