The utilization of spirocyclic scaffolds in novel drug discovery

Zheng, Ya-Jun; Tice, Colin M.

doi:10.1080/17460441.2016.1195367

Cited by 210 publications

(151 citation statements)

References 26 publications

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“…The results here demonstrate that an alternative enzymatic route to these compounds is feasible. Furthermore, the rigidity and three-dimensional nature of spirocycles makes them attractive moieties in drug discovery41, and a facile enzymatic approach to such structures will be of use in the future.…”

Section: Discussionmentioning

confidence: 99%

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

et al. 2017

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The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1′-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1′-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1′-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

et al. 2017

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“…Within three‐dimensional fragment space, spirocycles are an important class of saturated ring systems , . The quaternary centre provides an inherent three‐dimensionality to this sub‐set of scaffolds whilst their cyclic nature provides all of the benefits of reduced flexibility.…”

Section: Introductionmentioning

confidence: 99%

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

et al. 2019

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In recent years the pharmaceutical industry has benefited from the advances made in fragment‐based drug discovery (FBDD) with more than 30 fragment‐derived drugs currently marketed or progressing through clinical trials. The success of fragment‐based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2‐rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three‐dimensional scaffolds. Herein, we report step‐efficient routes to a number of biologically relevant, fragment‐like heterocyclic spirocycles. The use of both electron‐deficient and electron‐rich 2‐atom donors was explored in complexity‐generating [3+2]‐cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.

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“…Such compounds are expected to interact more efficiently with binding pockets in proteins, which are three-dimensional in nature, and have better solubility, a crucial property in the process of drug development [3]. Spiro compounds are very attractive in this connection, since they are intrinsically three-dimensional and many bioactive natural products contain spirocyclic cores that can be assumed to have arisen in the course of evolution to allow better interaction with proteins [4]. In particular, spiro-oxindolepyrrolidine cores can be found in a variety of alkaloids [5], including elacomine, rhynchophylline and the spirotryprostatins, among many others.…”

Section: Introductionmentioning

confidence: 99%

Regio and stereoselective synthesis of anticancer spirooxindolopyrrolidine embedded piperidone heterocyclic hybrids derived from one-pot cascade protocol

Arumugam

Almansour

Al‐thamili

et al. 2018

Chemistry Central Journal

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BackgroundSpiropyrrolidine tethered piperidone heterocyclic hybrids were synthesized with complete regio- and stereoselectively in excellent yield via a tandem three-component 1,3-dipolar cycloaddition and subsequent enamine reaction in [bmim]Br. The synthesized compounds were evaluated for their anticancer activity against FaDu hypopharyngeal tumor cells.FindingsInterestingly, most compounds displayed cytotoxicities similar to the standard anticancer agent bleomycin, with two of them (5a and 5g) being slightly more active than the reference drug.ConclusionSynthesized compounds have also been evaluated for their apoptosis-inducing properties in a cancer cell model, finding that treatment with compounds 5a–e led to apoptotic cell death.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0462-x) contains supplementary material, which is available to authorized users.

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The utilization of spirocyclic scaffolds in novel drug discovery

Cited by 210 publications

References 26 publications

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

Regio and stereoselective synthesis of anticancer spirooxindolopyrrolidine embedded piperidone heterocyclic hybrids derived from one-pot cascade protocol

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