Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

Cordier, C.; Morton, Daniel; Murrison, Sarah; Nelson, Adam; O’Leary-Steele, Catherine

doi:10.1039/b706296f

Cited by 198 publications

(78 citation statements)

References 64 publications

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“…This collection can also be readily expanded by harnessing the powerful capabilities of biosynthetic machinery using, for example, phage display (2), engineered biosynthesis (3)(4)(5), and synthetic biology. Complementing nature's library, fully synthetic libraries (6,7) offer the notable advantage of being derivable from a more varied collection of bond construction methods, atoms, and building blocks than those used in nature. Virtual libraries (8,9) provide a third and comprehensive source of lead structures and are limited only by bonding theory and self-imposed structure generation and selection criteria.…”

mentioning

confidence: 99%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

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mentioning

confidence: 99%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…[25] As such we envisage that this methodology will prove useful in a wide synthetic context, with possible applications in both target-oriented and diversity-oriented synthesis. [26] Experimental Section General experimental procedure for medium-ring biaryl synthesis: Ethylene glycol (2 mL per mmol substrate) was added to a mixture of the acyclic precursor (1 equiv), Cs 2 CO 3 (2 equiv) and CuI (0.1 equiv). The reaction mixture was stirred at 100 8C for 3 h, cooled to room temperature and filtered through Celite.…”

Section: Resultsmentioning

confidence: 99%

Novel and Efficient Copper‐Catalysed Synthesis of Nitrogen‐Linked Medium‐Ring Biaryls

Kenwright

Galloway

Blackwell

et al. 2011

Chemistry A European J

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Herein, a new copper-catalysed strategy for the synthesis of rare nitrogen-linked seven-, eight- and nine-membered biaryl ring systems is described. It is proposed that the reaction proceeds through a highly activated intramolecularly co-ordinated copper catalyst. The process is technically simple, proceeds under relatively mild conditions, displays a broad substrate scope and forms biologically valuable products that are difficult to synthesise by other methods. We envisage that this methodology will prove useful in a wide synthetic context, with possible applications in both target-oriented and diversity-oriented synthesis.

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“…Modern approach diversifies the synthesis and explores a wider chemical space. 3,4 b-Carboline alkaloids, saturated or unsaturated, both of them have been reported to be active against either HSV-1 or HSV-2 or both (Figure in supporting information).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of multi ring-fused imidazo [1,2-a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent

Chakravarty

Ojha

Konreddy

et al. 2015

Antivir Chem Chemother

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Background: Natural product-inspired synthesis is a key incorporation in modern diversity-oriented synthesis to yield biologically novel scaffold. Inspired by b-carboline fused system, we have designed molecules with multi ring fused scaffold by modifying the tricyclic pyrido [3,4-b]indole ring with imidazo[1,2-a]isoquinoline. Methods: A highly convergent approach with new C-N and C-C bond formation to synthesize multiring fused complex scaffold imidazo[1,2-a]isoquinolinies as fluorophores. N-nucleophile-induced ring transformation of 2H-pyran-2-one followed by in situ cis-stilbene-type oxidative photocyclization yielded new C-C bond formation without additional oxidant. The cytotoxicity, effective concentrations, and the mode of action of the synthesized analogs were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),, plaque reduction, time of addition, and reverse transcriptase Polymerase Chain Reaction (PCR). Results: Novel imidazo[1,2-a]isoquinoline analogs were prepared, and the results revealed that trans isomer of cyclopropyl analog (EC 50 35 and 37.5 mg/ml) and trans isomer of citric acid salt of phenyl analog (EC 50 38.2 and 39.8 mg/ml) possess significant anti-Herpes Simplex Virus (HSV) activity with selectivity index of >10. The kinetic study demonstrated that both the analogs inhibited HSV-1F and HSV-2G at 2-4 h postinfection. Finally, western blot and reverse transcriptase PCR assays revealed that both the analogs suppressed viral immediate early transcription. Conclusion: Novel imidazo[1,2-a]isoquinoline analogs were synthesized from pyranone with appropriate amines. Two compounds showed better antiviral profile on HSV-infected Vero cells, compared to the standard drug acyclovir (ACV). Overall, we discovered a promising scaffold to develop a nonnucleoside lead targeting the viral immediate early transcription for the management of HSV infections.

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Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

Abstract: This review describes how the structures of natural products have provided an insipration for new synthetic methodology which yields libraries of diverse bioactive compounds.

Cited by 198 publications

References 64 publications

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Novel and Efficient Copper‐Catalysed Synthesis of Nitrogen‐Linked Medium‐Ring Biaryls

Synthesis of multi ring-fused imidazo [1,2-a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent

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