PyBOP® and PyBroP: Two reagents for the difficult coupling of the α,α-dialkyl amino acid, Aib.

Frérot, Eric; Coste, J. H.; Pantaloni, A.; Dufour, Marie-Noëlle; Jouin, Patrick

doi:10.1016/s0040-4020(01)80922-4

Cited by 226 publications

(120 citation statements)

References 25 publications

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“…PyBOP coupling 99 1 equiv of an amino component and 1 equiv of the carboxyl derivative were dissolved in DMF (5 mL/mmol) and treated with 1 equiv PyBOP and 2-3 equiv DIPEA to reach a pH value between 8.5 and 9.5. The mixture was stirred at 0 °C for 30 minutes and at RT for 2 h. The solvent was removed in vacuum.…”

Section: Methods Fmentioning

confidence: 99%

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

et al. 2013

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A series of new substrate analogue inhibitors of the WNV NS2B–NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans‐(4‐guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro‐substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 μM were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin‐like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4‐dichlorophenylacetyl‐Lys‐Lys‐GCMA (Ki=0.13 μM). The inhibitor adopts a horseshoe‐like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development.

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Section: Methods Fmentioning

confidence: 99%

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

et al. 2013

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“…As usual, the Gly residue was introduced first; then the glycyl-peptide resin was subjected to reductive alkylation using the corresponding alkylaldehyde and NaCNBH 3 in 1% AcOH/DMF. 10) For synthesis of [N-guanidinopropyl-Gly 2 ]YRFB (2), the H-Gly-Phe-bAla-MBHA resin was alkylated with three equivalents of and NaCNBH 3 in 1% AcOH/DMF as is usual 10) and then reacted with Fmoc-Tyr-OH in the presence of PyBOP/ HOBt 17) in DMF. After the removal of Boc-group with 0.5 M methanesulfonic acid/DCM, the amino group was guanylated using 3,5-dimethylpyrazole-1-carboxamidine nitrate in DIPEA/DMF.…”

Section: )mentioning

confidence: 99%

Novel [D-Arg2]dermorphin(1-4) Analogs with .MU.-Opioid Receptor Antagonist Activity.

Ambo

Terashima

Sasaki

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…We investigated several other amide coupling reagents (Table 1). Significant amounts of dimeric tadalafil analogues 2a and trans-2a were obtained when bromo-trispyrrolidino-phosphonium hexafluorophosphate (PyBroP) 24) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) were used to activate diacid 8a (Table 1, Entries 1-5). 25) Further investigation revealed that among the reagents examined, 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (HATU) was the most efficient in producing these dimeric tadalafil analogues 2a and trans-2a in moderate to good yields (Table 1, Entries 6-10).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

Mandava

Ganganna

Hwang

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.Key words phosphodiesterase 5 inhibitor; bisprehomotadalafil; bisprecyclopentyltadalafil; bisprenortadalafil; dietary supplement Tadalafil (1, Cialis ® ), a phosphodiesterase 5 (PDE5) inhibitor, has been widely used for the treatment of erectile dysfunction (ED). In spite of its excellent efficacy and safety profile, the administration of tadalafil (1) to patients who are concurrently using any form of organic nitrates or guanylate cyclase stimulators is contraindicated due to its hypotensive effects. 1-3)Tadalafil (1) should also not be prescribed in patients with Stevens-Johnson syndrome or exfoliative dermatitis because hypersensitivity reactions to this ED drug have been reported in such patients. 4) However, tadalafil (1) and its analogues have been detected in a number of dietary supplements over the last decade. These illegal products are mainly advertised as sexual enhancement products and sold without any declarations on the label of the pharmacological and toxicological effects arising from the PDE5 inhibitory activity. Most of the tadalafil analogues detected in illegal dietary supplements were generated by removal of an N-methyl group or its replacement by another group such as amino, ethyl, butyl, octyl or cyclopentyl.5-14) Epimeric tadalafil analogues 5,15) and precursor-related analogues of tadalafil (1) have also been identified.16-18) These analogues were presumably designed for use in adulteration to avoid identification by authorities. Recently, we found a new type of tadalafil analogues in dietary supplements, exemplified by 2a,b and 3, which bear two (pre) tadalafil moieties (Fig. 1). We have named these trans-bisprehomotadalafil, trans-bisprecyclopentyltadalafil and bisprenortadalafil, respectively. 5,19,20) The relative stereochemistry of these dimeric analogues was tentatively assigned based on no observation of nuclear Overhauser effect (NOE) between the protons at stereogenic centers in the molecules and by comparison of their spectral data with those of monomeric tadalafil der...

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PyBOP® and PyBroP: Two reagents for the difficult coupling of the α,α-dialkyl amino acid, Aib.

Cited by 226 publications

References 25 publications

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

Novel [D-Arg2]dermorphin(1-4) Analogs with .MU.-Opioid Receptor Antagonist Activity.

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements

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