Chlorizidine, a Cytotoxic 5H-Pyrrolo[2,1-a]isoindol-5-one-Containing Alkaloid from a Marine Streptomyces sp.

Alvarez-Mico, Xavier; Jensen, Paul R.; Fenical, William; Hughes, Chambers C.

doi:10.1021/ol303374e

Cited by 61 publications

(73 citation statements)

References 32 publications

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“…12 In this study, we demonstrate how this 'tag-transfer' concept works through studies on the marinopyrrole natural products. 13,14 The final two case studies on the seriniquinone 15 and chlorizidine 16,17 natural products define how further extension into downstream and cell cycle markers allows one to develop a streamlined connectivity between cellular processing, its associated molecular targets, and ultimate downstream effects.…”

Section: Resultsmentioning

confidence: 99%

“…strain CNH287. 17 Cultivation of this strain a seawater-based medium followed by solid phase extraction with Amberlite XAD-18 resin and fractionation on silica gel resulted in one fraction with significant cytotoxicity against HCT-116 cells. Isolation by C18 reversed-phase HPLC, we were able to identify a cytotoxic metabolite, chlorizidine A (Figure 2), with a prominent UV-Vis profile.…”

Section: Case Study 4: Chlorizidine a Targets Glycolysismentioning

confidence: 98%

“…Using a combination of 2D-NMR and X-ray crystallography, we were able to assign the structure of chlorizidine A, as shown in Figure 2. 17 The targets and MOA of chlorizidin A were further analyzed using an IAF probe ( Figure 6) in HCT-116 cells. 16 Confocal microscopic analysis indicated that the probe was rapidly taken up in the cytosol, and after 10 h treatment, chlorizidine IAF probe ( Figure 6) was observed in the lysosomes, as confirmed by its co-localization with LysoTracker red DND-99 (Figure 6c).…”

Section: Case Study 4: Chlorizidine a Targets Glycolysismentioning

confidence: 99%

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Elucidating the Mode of Action of Marine Natural Products through an Immunoaffinity Fluorescent (IAF) Approach

Clair

Fenical

Costa-Lotufo

2016

Journal of the Brazilian Chemical Society

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Understanding the target and mode of action (MOA) of small molecules activity has become a critical feature in guiding the transition between drug discovery and clinical evaluation. While classically placed at the latter stages of a discovery program, we now describe how addressing the mode of action of natural products at the early stages of a program provides an important vehicle to inform the drug discovery process. In this review, we outline a streamlined cellular and molecular biological system and explore its utility through a series of four cases studies. We believe that this approach offers critical lessons to guide future drug discovery programs.

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Section: Resultsmentioning

confidence: 99%

Section: Case Study 4: Chlorizidine a Targets Glycolysismentioning

confidence: 98%

Section: Case Study 4: Chlorizidine a Targets Glycolysismentioning

confidence: 99%

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Elucidating the Mode of Action of Marine Natural Products through an Immunoaffinity Fluorescent (IAF) Approach

Clair

Fenical

Costa-Lotufo

2016

Journal of the Brazilian Chemical Society

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“…122 Figure 15A). [161][162][163] The peptidyl carrier protein (PCP) tethered substrates of Clz5, PltA and HalB are all derived from oxidation of proline-S-PCP intermediates in NRPS or NRPS-PKS assembly lines. Genome mining of the marine organisms responsible for the biosynthesis of brominated marine natural products has led to the identification of an interesting pyrrole Fl-Hal, Bmp2, from…”

Section: Flavin-dependent Pyrrole Halogenasesmentioning

confidence: 99%

Development of Halogenase Enzymes for Use in Synthesis

Latham

Brandenburger

Shepherd³

et al. 2017

Chem. Rev.

285

244

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Nature has evolved halogenase enzymes to regioselectively halogenate a diverse range of biosynthetic precursors, with the halogens introduced often having a profound effect on the biological activity of the resulting natural products. Synthetic endeavours to create non-natural bioactive small molecules for pharmaceutical and agrochemical applications have also arrived at a similar conclusion -halogens can dramatically improve the properties of organic molecules for selective modulation of biological targets in vivo. Consequently a high proportion of pharmaceuticals and agrochemicals on the market today possess halogens. Halogenated organic compounds are also common intermediates in synthesis and are particularly valuable in metal catalyzed cross-coupling reactions.Despite the potential utility of organohalogens, traditional non-enzymatic halogenation chemistry utilizes deleterious reagents and often lacks regiocontrol. Reliable, facile and cleaner methods for the regioselective halogenation of organic compounds are therefore essential in the development of economical and environmentally-friendly industrial processes. A potential avenue towards such methods is the use of halogenase enzymes, responsible for the biosynthesis of halogenated natural products, as biocatalysts. This review will discuss the advances towards this goal thus far, in addition to untapped potential sources of such biocatalysts and how further development of the enzymes may be focused in order to achieve the goal of industrial scale biohalogenation.

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“…CNH-287. 46 Moore and co-workers described how 11 is derived from the starter unit 8 . Extension of this with malonyl-CoA is mediated by a dedicated FabF, Clz11, which acts in parallel with primary metabolic FAS enzymes resulting in a fully saturated acyl chain.…”

Section: Polyketide Extender Unitsmentioning

confidence: 99%

Recent advances in the biosynthesis of unusual polyketide synthase substrates

Ray

Moore

2016

Nat. Prod. Rep.

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Covering: 2003 to July 2015 for polyketide synthase starter units and 2012 to September 2015 for polyketide synthase extender units This highlight provides an overview of recent advances in understanding the diversity of polyketide synthase (PKS) substrate building blocks. Substrates functioning as starter units and extender units contribute significantly to the chemical complexity and structural diversity exhibited by this class of natural products. This article complements and extends upon the current comprehensive reviews that have been published on these two topics (Moore and Hertweck, Nat. Prod. Rep., 2002, 19, 70; Chan et. al., Nat. Prod. Rep., 2009, 1, 90; Wilson and Moore, Nat. Prod. Rep., 2012, 29, 72).

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Chlorizidine, a Cytotoxic 5H-Pyrrolo[2,1-a]isoindol-5-one-Containing Alkaloid from a Marine Streptomyces sp.

Cited by 61 publications

References 32 publications

Elucidating the Mode of Action of Marine Natural Products through an Immunoaffinity Fluorescent (IAF) Approach

Elucidating the Mode of Action of Marine Natural Products through an Immunoaffinity Fluorescent (IAF) Approach

Development of Halogenase Enzymes for Use in Synthesis

Recent advances in the biosynthesis of unusual polyketide synthase substrates

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