Insights into drug discovery from natural products through structural modification

Chen, Jichao; Li, Wenlong; Yao, Hequan; Xu, Jinyi

doi:10.1016/j.fitote.2015.04.012

Cited by 111 publications

(68 citation statements)

References 123 publications

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“…[4] Furthermore,s ynthetic derivatives of natural products might exhibiti mprovedp harmacologicalp roperties compared to the natural variant. [5] With this in mind, it is desirable to develop flexible synthetic routes that providea sm any derivatives of at arget structure as possiblefrom onecommon precursor.…”

mentioning

confidence: 99%

Total Synthesis of Keramamides A and L from a Common Precursor by Late‐Stage Indole Synthesis and Configurational Revision

Junk

Kazmaier

2018

Angew Chem Int Ed

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The marine natural products keramamide A and L, members of the class of anabaenopeptin-type peptides, were synthesized for the first time by a convergent and flexible route. The installation of the substituted tryptophan moieties was accomplished at the very end of the synthesis on the cyclic peptides, and thus enabled the synthesis of both natural products from one common precursor. The preparation of several epimers clearly indicates that the originally proposed relative configurations of both Keramamides A and L were not correct.

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mentioning

confidence: 99%

Total Synthesis of Keramamides A and L from a Common Precursor by Late‐Stage Indole Synthesis and Configurational Revision

Junk

Kazmaier

2018

Angew Chem Int Ed

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“…Post-modifications of natural compounds is one of the approaches to enhance the biological and pharmaceutical properties of parent molecules [23]. In this research, we produced three umbelliferone derivatives using a monooxygenase, a glycosyltransferase, and a methyltransferase enzyme via microbial biotransformation in E. coli .…”

Section: Discussionmentioning

confidence: 99%

Synthesis of umbelliferone derivatives in Escherichia coli and their biological activities

et al. 2017

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BackgroundUmbelliferone, also known as 7-hydroxycoumarin, is a phenolic metabolite found in many familiar plants. Its derivatives have been shown to have various pharmacological and chemo-preventive effects on human health. A uridine diphosphate glycosyltransferase YjiC from Bacillus licheniformis DSM 13, a cytochrome P450BM3 (CYP450 BM3) variant namely mutant 13 (M13) from Bacillus megaterium, and an O-methyltransferase from Streptomyces avermitilis (SaOMT2) were used for modifications of umbelliferone.ResultsThree umbelliferone derivatives (esculetin, skimmin, and herniarin) were generated through enzymatic and whole cell catalysis. To improve the efficiencies of biotransformation, different media, incubation time and concentration of substrate were optimized and the production was scaled up using a 3-L fermentor. The maximum yields of esculetin, skimmin, and herniarin were 337.10 μM (67.62%), 995.43 μM (99.54%), and 37.13 μM (37.13%), respectively. The water solubility of esculetin and skimmin were 1.28-folds and 3.98-folds as high as umbelliferone, respectively, whereas herniarin was 1.89-folds less soluble than umbelliferone. Moreover, the antibacterial and anticancer activities of herniarin showed higher than umbelliferone, esculetin and skimmin.ConclusionsThis study proves that both native and engineered enzymes could be employed for the production of precious compounds via whole cell biocatalysis. We successfully produced three molecules herniarin, esculetin and skimmin in practical amounts and their antibacterial and anticancer properties were accessed. One of the newly synthesized molecules the present research suggests that the combinatorial biosynthesis of different biosynthetic enzymes could rapidly promote to a novel secondary metabolite.Electronic supplementary materialThe online version of this article (doi:10.1186/s13036-017-0056-5) contains supplementary material, which is available to authorized users.

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“…While continuously isolating, [3] screening, [4] and/orb ioengineering [5] natural products as small molecule ligandsr emains critical for identifying new biological activities and targets, the structuralm odification of naturalp roducts hasr eceived much attention from the synthetic, medicinal, and biological com-munities. [6][7][8][9][10] These natural product derivatives would preferably possess an enhanceda ctivity and selectivity,o rp ossibly,a n entirely alteredb ioactivity from that of the parent natural products. [11][12][13][14][15][16] We have been interested in the bioactive marine natural product ageladine A( 1)a nd its analogous 2-aminoimidazopyridine alkaloids ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

One‐Pot Evolution of Ageladine A through a Bio‐Inspired Cascade towards Selective Modulators of Neuronal Differentiation

Iwata

Otsuka

Tsubokura

et al. 2016

Chemistry A European J

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A bio-inspired cascade reaction has been developed for the construction of the marine natural product ageladine A and a de novo array of its N1-substituted derivatives. This cascade features a 2-aminoimidazole formation that is modeled after an arginine post-translational modification and an aza-electrocyclization. It can be effectively carried out in a one-pot procedure from simple anilines or guanidines, leading to structural analogues of ageladine A that had been otherwise synthetically inaccessible. We found that some compounds out of this structurally novel library show a significant activity in modulating the neural differentiation. Namely, these compounds selectively activate or inhibit the differentiation of neural stem cells to neurons, while being negligible in the differentiation to astrocytes. This study represents a successful case in which the native biofunction of a natural product could be altered by structural modifications.

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Insights into drug discovery from natural products through structural modification

Cited by 111 publications

References 123 publications

Total Synthesis of Keramamides A and L from a Common Precursor by Late‐Stage Indole Synthesis and Configurational Revision

Total Synthesis of Keramamides A and L from a Common Precursor by Late‐Stage Indole Synthesis and Configurational Revision

Synthesis of umbelliferone derivatives in Escherichia coli and their biological activities

One‐Pot Evolution of Ageladine A through a Bio‐Inspired Cascade towards Selective Modulators of Neuronal Differentiation

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