A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings

Zhao, Chang‐Qiu; Ye, Zhengqing; Ma, Zewei; Wildman, Scott A.; Blaszczyk, Stephanie A.; Hu, Lihong; Guizei, Ilia A.; Tang, Weiping

doi:10.1038/s41467-019-11976-2

Cited by 82 publications

(82 citation statements)

References 54 publications

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“…However, medium‐sized carbo‐ and heterocycles are found in numerous natural products with selected illustrative examples shown in Figure . Considering the success rates of natural products as drug leads, such cyclic frameworks have emerged as a privileged platform on which synthetic compound libraries can be built for lead generation in drug discovery . Their particular suitability for interrogation of protein targets could intuitively be rationalized, on one hand, by their higher degree of conformational flexibility compared to the smaller‐sized counterparts, and, therefore, higher chances of adopting a protein‐binding conformation.…”

Section: Introductionmentioning

confidence: 99%

An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene‐Fused [1.4]Oxazepines

et al. 2020

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A four‐step approach to the “hydrated imidazoline ring expansion” (HIRE) is presented. In most cases, the ring expansion was the sole process. However, for the first time, an alternative course of the hydrated imidazoline evolution was discovered which gave N‐aminoethyl derivatives. These can, in principle, be converted into the target HIRE products under sufficiently forcing conditions. The approach offers improved flexibility with respect to the peripheral substituents and is also applicable to the synthesis of eleven‐membered lactams. We observed that the latter can exist in two stable isomeric forms due to lactam–amide bond isomerization. The latter finding further demonstrates the value of medium‐sized rings as multiple‐conformer probes for biological target interrogation.

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Section: Introductionmentioning

confidence: 99%

An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene‐Fused [1.4]Oxazepines

et al. 2020

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“…Natural products provide a wealth of valuable natural resources for modern medicine and are seen as promising and popular candidates for drug repositioning studies [ 47 ]. Their natural scaffold novelty, structural complexity, abundant stereochemistry and ‘metabolite-likeness’ mainly account for their broad-spectrum of biological activities [ 48 , 49 ]. The multi-targeting and synergistic effects of natural products exhibit great advantages in treating diseases undergoing sophisticated mechanisms, such as fibrosis [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Dr AFC: drug repositioning through anti-fibrosis characteristic

Gao

et al. 2020

Briefings in Bioinformatics

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Fibrosis is a key component in the pathogenic mechanism of a variety of diseases. These diseases involving fibrosis may share common mechanisms and therapeutic targets, and therefore common intervention strategies and medicines may be applicable for these diseases. For this reason, deliberately introducing anti-fibrosis characteristics into predictive modeling may lead to more success in drug repositioning. In this study, anti-fibrosis knowledge base was first built by collecting data from multiple resources. Both structural and biological profiles were then derived from the knowledge base and used for constructing machine learning models including Structural Profile Prediction Model (SPPM) and Biological Profile Prediction Model (BPPM). Three external public data sets were employed for validation purpose and further exploration of potential repositioning drugs in wider chemical space. The resulting SPPM and BPPM models achieve area under the receiver operating characteristic curve (area under the curve) of 0.879 and 0.972 in the training set, and 0.814 and 0.874 in the testing set. Additionally, our results also demonstrate that substantial amount of multi-targeting natural products possess notable anti-fibrosis characteristics and might serve as encouraging candidates in fibrosis treatment and drug repositioning. To leverage our methodology and findings, we developed repositioning prediction platform, drug repositioning based on anti-fibrosis characteristic that is freely accessible via https://www.biosino.org/drafc.

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“…Natural products provide a wealth of valuable natural resources for modern medicine and are seen as promising and popular candidates for drug repositioning studies[47]. Their privileged scaffolds, structural complexity, abundant stereochemistry and ‘metabolite-likeness’ are main reasons for the broad-spectrum of biological activities [48, 49]. The multi-targets and synergistic effects of natural products exhibit great advantages in treating diseases undergoing sophisticated mechanisms, such as fibrosis[50].…”

Section: Discussionmentioning

confidence: 99%

DrAFC: Drug Repositioning Through Anti-Fibrosis Characteristic

Gao

et al. 2020

Preprint

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16Fibrosis is a key component in the pathogenic mechanism of many diseases. These 17 diseases involving fibrosis may share common mechanisms, therapeutic targets and 18 therefore, common intervention strategies and medicines may be applicable for these 19 diseases. For this reason, deliberately introducing anti-fibrosis characteristics into 20 modelling may lead to more success in drug repositioning. In this study, anti-fibrosis 21 knowledge base was first built by collecting data from multiple resources. Both 22 structural and biological profiles were derived from the knowledge base and used for 23 constructing machine learning models including Structural Profile Prediction Model 24 (SPPM) and Biological Profile Prediction Model (BPPM). Three external public data 25 sets were employed for validation purpose and further exploration of potential 26 repositioning drugs in wider chemical space. The resulting SPPM and BPPM models 27 achieve area under the receiver operating characteristic curve (AUC) of 0.879 and 28 0.972 in the training set, and 0.814 and 0.874 in the testing set. Additionally, our 29 results also demonstrate that substantial amount of multi-targeting natural products 30 possess notable anti-fibrosis characteristics and might serve as encouraging candidates 31 in fibrosis treatment and drug repositioning. To leverage our methodology and 32 findings, we developed repositioning prediction platform, Drug Repositioning based 33 on Anti-Fibrosis Characteristic (Dr AFC) that is freely accessible via 34 https://www.biosino.org/drafc. 35 36

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A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings

Cited by 82 publications

References 54 publications

An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene‐Fused [1.4]Oxazepines

An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene‐Fused [1.4]Oxazepines

Dr AFC: drug repositioning through anti-fibrosis characteristic

DrAFC: Drug Repositioning Through Anti-Fibrosis Characteristic

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