Enantioselective Spirocyclizations from Tryptophanol-Derived Oxazolopiperidone Lactams

Amat, Mercedes; Santos, Maria M. M.; Gómez, Antonia M.; Jokic, Danica; Molins, Elı́es; Bosch, Joan

doi:10.1021/ol0712327

Cited by 35 publications

(20 citation statements)

References 27 publications

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“…1, were synthesized according to the described procedures [9][10][11]. Nutlin-3a was from Alexis Biochemicals (Grupo Taper, Sintra, Portugal); doxorubicin and SJ-172550 were from Sigma-Aldrich (Sintra, Portugal); etoposide was from Calbiochem (VWR, Carnaxide, Portugal).…”

Section: Compoundsmentioning

confidence: 99%

“…These compounds contain an oxazolo ring fused with a piperidinone ring, two scaffolds that are described to act as p53-MDM2 interaction inhibitors [8,13]. Compounds OXAZ-2, OXAZ-3, OXAZ-4, and OXAZ-5 were synthesized by cyclocondensation reaction of (S)-tryptophanol and the appropriate ␦-oxo-esters [8][9][10]. The lactams OXAZ-3 and OXAZ-5 were converted to the (S)-tryptophanol derivatives OXAZ-6 and OXAZ-1, respectively, with high yields [10].…”

Section: 1mentioning

confidence: 99%

“…Compounds OXAZ-2, OXAZ-3, OXAZ-4, and OXAZ-5 were synthesized by cyclocondensation reaction of (S)-tryptophanol and the appropriate ␦-oxo-esters [8][9][10]. The lactams OXAZ-3 and OXAZ-5 were converted to the (S)-tryptophanol derivatives OXAZ-6 and OXAZ-1, respectively, with high yields [10]. In the yeast assays used in this work the human p53 retains its function as a transcription factor inducing a marked growth inhibition, which is abolished by human MDM2 and MDMX.…”

Section: 1mentioning

confidence: 99%

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A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

Soares

Raimundo

Pereira

et al. 2015

Pharmacological Research

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Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53(+/+)) and its p53-null isogenic derivative (HCT116 p53(-/-)), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53(+/+), but not in p53(-/-), HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMX-overexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53(+/+) cells, the disruption of the p53 interaction with MDMs by OXAZ-1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs. Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53-MDMs interaction.

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Section: Compoundsmentioning

confidence: 99%

Section: 1mentioning

confidence: 99%

Section: 1mentioning

confidence: 99%

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A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

Soares

Raimundo

Pereira

et al. 2015

Pharmacological Research

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“…As well, reductive ring cleavage of the oxazolidine 207b by treatment with titanium tetrachloride and Et 3 SiH, which is promoted diastereoselective reductive reaction, afforded the α‐amidoalkylation product 225 rather than the reduction of the N ‐acyliminium cation intermediate. In addition, the deactivated N ‐tosyl lactam 207c underwent α‐amidoalkylation at C3 of indole nucleus under the same previous conditions to afford the spiro analogue 227 (Scheme ) …”

Section: Reactionsmentioning

confidence: 99%

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

Monier

Abdel-Latif

El‐Mekabaty

et al. 2019

Journal of Heterocyclic Chem

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The present study demonstrates a synopsis of the scientific researches reported on the different reactions of oxazolo[3,2‐a]pyridines, besides the preparation of significant fused heterocycles up till now. The different main sections that described the reactivity of the inspected analogues include stereoselective alkylation, reactions involved oxazolidine ring, synthesis of polycyclic systems, indole alkaloids, and alkyl amines. The stereochemical selectivity of oxazolopiperidone lactams is studied, in which the configuration of the stereocenter C8a and substituents at the C8 and C8a effect on the stereoselectivity. On the other hand, the synthetic consequence of the alkylation products provides diverse routes for the synthesis of substituted enantiopure piperidines that are used for the synthesis of natural products, for example, (−)‐rhazinilam, (+)‐eburnamonine, (+)‐aspidospermidine, indole alkaloids such as dihydrocleavamine, nor‐20‐epiuleine, (+)‐dasycarpidone, (+)‐uleine, indoloquinolizidine, (+)‐dihydrocorynantheine, (−)‐dihydrocorynantheol, and indolizines, eg, octahydroindolizines, monomorine I, (−)‐S‐coniceine, and (−)‐R‐coniceine.

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“…The decisive role of the hydroxymethyl group for the stereoselectivity was demonstrated, because a similar lactam lacking the ethyl substituent α to the iminium cation gave a single enantiopure spiro derivative in excellent yield. [65] Scheme 40. This stereoselective spyrocyclization expands the potential of oxazolopiperidone lactams as chiral building blocks for the synthesis of complex piperidine systems. [66] The possibility of using more complex oxo acid derivatives in the synthesis of chiral oxazolo lactams has allowed an elegant, highly stereoselective approach to the tetracyclic erythrinane core, as shown in Schemes 41 [67] and 42.…”

Section: Stereochemical Aspects -Diastereoselective α-Amidoalkylationmentioning

confidence: 99%

Strategies Based on Aryllithium and N‐Acyliminium Ion Cyclizations for the Stereocontrolled Synthesis of Alkaloids and Related Systems

et al. 2011

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The intramolecular α-amidoalkylation reactions of aromatic and heteroaromatic ring systems constitute a versatile approach for the synthesis of nitrogen heterocyles in a diastereoselective or enantioselective fashion. On the other hand, the intramolecular reactions of aryllithium compounds have also been extensively used in the synthesis of carbocycles and heterocycles. The use of imides as internal electrophiles is particularly attractive because of the potential to introduce diverse functionality into the cyclized products by subjecting the resulting α-hydroxylactams to intermolecular IntroductionAryllithium compounds and N-acyliminium ions are extremely versatile intermediates for the formation of carboncarbon bonds in organic synthesis. Cyclization of aryllithium compounds generated by halogen/lithium exchange with internal electrophiles (Parham cyclization) has become a valuable protocol for the stereoselective construction of carbocyclic and heterocyclic systems.[1] Many electrophiles remain inert during halogen/metal exchange reaction at low temperature, but are reactive enough to participate in a subsequent cyclization reaction. Halides, epoxides, or alkenes [2] are thus among the different types of internal electrophiles used in the Parham cyclization. When the internal electrophile is a carboxylate derivative, this anionic cyclization could be considered an anionic Friedel-Crafts equivalent, with the advantage that it lacks the electronic requirements of the classical reaction. Although it is possible to use carboxylic acids [3] or esters, [4] carbamates have proven to be much more effective internal electrophiles in Parham cycliacylations.[5] Amides are also useful electrophiles in Parham cyclizations, and it has been reported that in some cases there is an influence of the natures of the substituents at the nitrogen atom on the course of the cyclization reaction. [6,7] [a] Departamento In connection with our interest in aromatic lithiation, we have developed an anionic cyclization approach directed towards the construction of the pyrrolo[1,2-b]isoquinolone core based on N-(o-halobenzyl)pyrrole-2-carboxamides, showing that Weinreb amides and morpholine amides function as excellent internal electrophiles.[8] This observation could be explained by assuming that halogen/lithium exchange could be favored by a complex-induced proximity effect (CIPE).[9] This concept has been invoked to explain other metal/metal, hydrogen/metal, or halogen/metal [10] exchange reactions. Lithium/halogen exchange would thus be favored first by coordination of the inducing organolithium compound with amide or carbamate groups, and then by stabilization of the resulting aryllithium compound. The better behavior of Weinreb and morpholine amides relative to N,N-diethyl amides could be attributed to the extra stabilization of the intermediate generated after cyclization through the formation of an internal chelate. The scope of these Parham-type cyclizations has been extended to the formation of seven-and eight-membered rings [8b] ...

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Enantioselective Spirocyclizations from Tryptophanol-Derived Oxazolopiperidone Lactams

Abstract: A straightforward synthetic route to enantiopure spiro[indole-3,3'-indolizidines] is reported. The key step is a Lewis acid promoted cyclization of a Na-tosyltryptophanol-derived oxazolopiperidone lactam in the presence of Et3SiH.

Cited by 35 publications

References 27 publications

A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

Strategies Based on Aryllithium and N‐Acyliminium Ion Cyclizations for the Stereocontrolled Synthesis of Alkaloids and Related Systems

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