Triurethane-Protected Guanidines and Triflyldiurethane-Protected Guanidines:  New Reagents for Guanidinylation Reactions

Feichtinger, Konrad; Sings, Heather L.; Baker, Tracy J.; Matthews, Kenneth S.; Goodman, Murray

doi:10.1021/jo9814344

Cited by 174 publications

(141 citation statements)

References 18 publications

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“…We readily synthesized ligand 1 by guanidilation of the O-protected, doubly bridged tetraaminomethylcalix [4]arene 2 (25) with N,NЈ-bis-(tert-butoxycarbonyl)guanidine NЉ-triflate (26) (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand

Gordo

Martos

Santos

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Protein p53 is a transcription factor crucial for cell cycle and genome integrity. It is able to induce both cell arrest when DNA is damaged and the expression of DNA repair machinery. When the damage is irreversible, it triggers apoptosis. Indeed, the protein, which is a homotetramer, is mutated in most human cancers. For instance, the inherited mutation p53-R337H results in destabilization of the tetramer and, consequently, leads to an organism prone to tumor setup. We describe herein a rational designed molecule capable of holding together the four monomers of the mutated p53-R337H protein, recovering the tetramer integrity as in the wild-type structure. Two ligand molecules, based on a conical calix[4]arene with four cationic guanidiniomethyl groups at the wider edge (upper rim) and hydrophobic loops at the narrower edge (lower rim), fit nicely and cooperatively into the hydrophobic clefts between two of the monomers at each side of the protein and keep the tetrameric structure, like molecular templates, by both ion-pair and hydrophobic interactions. We found a good agreement between the structure of the complex and the nature of the interactions involved by a combination of theory (molecular dynamics) and experiments (circular dichroism, differential scanning calorimetry and 1 H saturation transfer difference NMR). molecular recognition ͉ multivalent calix[4]arene ligands ͉ oligoprotein stabilization ͉ protein-protein interactions

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Section: Resultsmentioning

confidence: 99%

Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand

Gordo

Martos

Santos

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…All solvents and other reagents were purchased from commercial sources and used without further purification. The mono-Boc amines were synthesized from the commercially available diamines by using a literature procedure (10 equiv of diamine and 1 equiv of Boc 2 O in chloroform followed by an aqueous work up to remove unreacted diamine) (35 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] (RQIKIWFQNRRMKWKK), and homopolymers of L-arginine (R5-R9) and D-arginine (r5-r9) were prepared with an automated peptide synthesizer (ABI433) by using standard solid-phase fluorenylmethoxycarbonyl (Fmoc) chemistry (36) with HATU as the peptide coupling reagent. The fluorescein moiety (Fl) was attached via an aminohexanoic acid spacer by treating a resin-bound peptide (1.0 mmol) with FITC (1.0 mmol) and diisopropyl ethyl amine (5 mmol) in dimethylformamide (DMF; 10 ml) for 12 h. Cleavage from the resin was achieved by using 95:5 trifluoroacetic acid (TFA)͞triisopropylsilane.…”

Section: Methodsmentioning

confidence: 99%

The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters

Wender

Mitchell

Pattabiraman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

1,509

1,446

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Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat49-57 (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat49-57 were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alaninesubstituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat49-57 play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat49-57 in cellular uptake. In contrast, a 9-mer of L-arginine (R9) was 20-fold more efficient than Tat49-57 at cellular uptake as determined by Michaelis-Menton kinetic analysis. The D-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat49-57 play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat49-57 and even to r9. Overall, a transporter has been developed that is superior to Tat49-57, protease resistent, and more readily and economically prepared.

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“…45 Di-Boc-triflylguanidine 110 and di -Cbz-triflylguanidine 113 are efficiently converted by various primary amines into guanidines 111, 114. [45][46][47] …”

Section: Triflyl Guanidinesmentioning

confidence: 99%

Recent developments in guanylating agents

Katritzky¹,

Rogovoy²

2005

Arkivoc

144

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Dedicated to Professor Nikolai Zefirov on the occasion of his 70th birthday (received 26 Oct 04; accepted 08 Jan 05; published on the web 05 Jan 05) AbstractGuanidines are important molecules with a wide range of interesting properties. In this overview we summarize recent advances in the development of guanylating reagents which we define as compounds forming a guanidine structure by a chemical transformation. We cover important classes of guanylating agents developed in the last two decades and representative examples are reported.

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Triurethane-Protected Guanidines and Triflyldiurethane-Protected Guanidines: New Reagents for Guanidinylation Reactions

Cited by 174 publications

References 18 publications

Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand

Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand

The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters

Recent developments in guanylating agents

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