Rapid construction of substituted 3-amino-1,5-benzothiazepin-4(5<i>H</i>)-one dipeptide scaffolds through an Ugi-4CR – Ullmann cross-coupling sequence

Poorten, Olivier Van der; Hauwe, Robin Van Den; Hollanders, Karlijn; Maes, Bert U. W.; Tourwé, Dirk; Jida, Mouhamad; Ballet, Steven

doi:10.1039/c7ob03094k

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…The turn-inducing properties of these peptidomimetics prove similar to previously reported benzothiazepinone dipeptides (Figure 1C). 59 Even though the latter have also been reported to adopt a -turn, [60][61][62] this conformation was not observed for any of the benzodiazepinones studied in this work.…”

Section: Scheme 5 Optimized Synthetic Pathway Towards 15-benzodiazepinone Ester Peptide Mimeticsmentioning

confidence: 51%

Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

Hauwe¹,

Elsocht²,

Hollanders³

et al. 2021

Synlett

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An efficient three step synthesis towards 3-amino-1,4-benzodiazepin-2-one derivatives is presented. The versatile Ugi-4-component reaction (Ugi-4CR) and Boc-deprotection is followed by a ligand-free Ullmann condensation. This protocol allows the rapid construction of a diverse array of substituted 1,5-benzodiazepinones. Since Ugi-based products are typically limited by their ‘inert’ C-terminal amides, the use of a convertible (‘cleavable’) isocyanide was envisaged and resulted in building blocks that can be made SPPS-compatible. To demonstrate the potential of this novel synthetic route, the design and preparation of novel phenylurea-1,5-bezondiazepin-4(5H)-one dipeptide mimetics with potential CCK2-antagonist properties is reported.

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Section: Scheme 5 Optimized Synthetic Pathway Towards 15-benzodiazepinone Ester Peptide Mimeticsmentioning

confidence: 51%

Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

Hauwe¹,

Elsocht²,

Hollanders³

et al. 2021

Synlett

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“…Compound formation was confirmed using the Wilson test; none of the synthetic reactions showed the positive response signified by the red coloration of concentrated sulphuric acid [35][36][37]. [1,4]thiazepin-4-yl)-6-iodo-4methylphenol (2b): White solid, Percentage yield: 89, m.p. 218-220 • C. IR (KBr):3176(OH), 3052(C-H arom), 1582 (C=N); 1 H NMR (300 MHz, DMSO-δ6):δ 10.39 (s, 1H, OH), δ 6.81-7.90 (m, 10H, ArH), 5.43 (dd, Hx, Jax = 10.79 Hz, Jbx = 2.10 Hz, 1H), 3.52 (dd, Hb, Jbx = 2.12 Hz, Jab = 14.1 Hz, 1H), 3.10 (dd, Ha, Jax = 10.81 Hz, Jab = 14.1 Hz, 1H), δ 2.72(s, 6H, (CH 3 ) 2, δ 2.39 (s, 3H, CH 3 ), δ 2.18 (s, 3H, CH 3 ), 13…”

Section: Methodsmentioning

confidence: 99%

“…BTZ derivatives have been found to have activity against different target proteins, and are of particular attention for lead development [2]. The BTZ nucleus has been used as a cardiovascular modulator acting on several G-protein coupled receptors as an antagonist [3], such as the antiarrhythmic (CCK) receptor [4], Angiotensin-Converting Enzyme [5], Angiotensin II receptor [6], etc. Hemodynamic effects, anti-cancer activity [7], and spasmolytic activity [8][9][10], as well as anti-ulcer activity [11], have recently been reported, as had a central nervous system depressant effect [12].…”

Section: Introductionmentioning

confidence: 99%

1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents

et al. 2022

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Considering the importance of benzothiazepine pharmacophore, an attempt was carried out to synthesize novel 1,5-benzothiazepine derivatives using polyethylene glycol−400 (PEG−400)-mediated pathways. Initially, different chalcones were synthesized and then subjected to a cyclization step with benzothiazepine in the presence of bleaching clay and PEG−400. PEG−400-mediated synthesis resulted in a yield of more than 95% in less than an hour of reaction time. Synthesized compounds 2a−2j were investigated for their in vitro cytotoxic activity. Moreover, the same compounds were subjected to systematic in silico screening for the identification of target proteins such as human adenosine kinase, glycogen synthase kinase−3β, and human mitogen-activated protein kinase 1. The compounds showed promising results in cytotoxicity assays; among the tested compounds, 2c showed the most potent cytotoxic activity in the liver cancer cell line Hep G−2, with an IC50 of 3.29 ± 0.15 µM, whereas the standard drug IC50 was 4.68 ± 0.17 µM. In the prostate cancer cell line DU−145, the compounds displayed IC50 ranges of 15.42 ± 0.16 to 41.34 ± 0.12 µM, while the standard drug had an IC50 of 21.96 ± 0.15 µM. In terms of structural insights, the halogenated phenyl substitution on the second position of benzothiazepine was found to significantly improve the biological activity. This characteristic feature is supported by the binding patterns on the selected target proteins in docking simulations. In this study, 1,5-benzothiazepines have been identified as potential anticancer agents which can be further exploited for the development of more potent derivatives.

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“…Multicomponent reactions (MCRs) have clear advantages with respect to conventional multistep reactions due to their potential to synthesize complicated organic molecules with low costs and quick reaction times [1,2]. It is common to use MCRs to obtain biologically relevant scaffold structures, mainly isocyanide-based MCRs, where the Ugi four component reaction (Ugi-4CR) has been particularly important for these endeavors [3,4,5,6,7,8]. Ugi-4CRs are easy and straightforward to perform; isocyanides derived from enantiopure α-amino acids (isocyanoacetates) could serve as substrates for this reaction.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors

et al. 2019

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Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities.

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Rapid construction of substituted 3-amino-1,5-benzothiazepin-4(5H)-one dipeptide scaffolds through an Ugi-4CR – Ullmann cross-coupling sequence

Cited by 6 publications

References 24 publications

Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents

Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors

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