Weapons in Disguise—Activating Mechanisms and Protecting Group Chemistry in Nature

Kwan, Jason C.; Luesch, Hendrik

doi:10.1002/chem.201001562

Cited by 13 publications

(12 citation statements)

References 85 publications

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“…The fact that the 28 S isomer, compound 3 , was isolated in much reduced yield compared with 1 suggests that 3 could be a minor side-product of the biosynthesis of 1 or else is an activated form (vide infra). (23)…”

Section: Resultsmentioning

confidence: 99%

“…However, it should be noted that the direct involvement of metals in the cytotoxicity of 1 − 3 was not demonstrated, and metal-independent major pleiotropic mechanisms of action for these compounds may exist. In light of previous examples of intricate protection/activation strategies in natural products,(23) a potential hypothesis is that compound 3 may represent an activated form of 1 , and this process may constitute a self-resistance strategy by the producing organism. We were unable to convert 1 to 3 under basic conditions, but this does not exclude conversion by a specific enzyme.…”

Section: Discussionmentioning

confidence: 99%

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Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides

et al. 2010

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Grassypeptolides A−C (1−3), a group of closely related bis-thiazoline containing cyclic depsipeptides, have been isolated from extracts of the marine cyanobacterium Lyngbya confervoides. Although structural differences between the analogues are minimal, comparison of the in vitro cytotoxicity of the series revealed a structure−activity relationship. When the ethyl substituent of 1 is changed to a methyl substituent in 2, activity is only slightly reduced (3−4-fold), whereas inversion of the Phe unit flanking the bis-thiazoline moiety results in 16−23-fold greater potency. We show that both 1 and 3 cause G1 phase cell cycle arrest at lower concentrations, followed at higher concentrations by G2/M phase arrest, and that these compounds bind Cu2+ and Zn2+. The three-dimensional structure of 2 was determined by MS, NMR, and X-ray crystallography, and the structure of 3 was established by MS, NMR, and chemical degradation. The structure of 3 was explored by in silico molecular modeling, revealing subtle differences in overall conformation between 1 and 3. Attempts to interconvert 1 and 3 with base were unsuccessful, but enzymatic conversion may be possible and could be a novel form of activation for chemical defense.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides

et al. 2010

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“…Prodrug strategies in general are quite commonly utilized by Nature. 192 Also, the presence of defined regions of the molecule that gives rise to biological activities toward mammalian cancer cells and bacterial or protozoan pathogens offers the opportunity for modulating potential off-target effects and improving the selectivity index.…”

Section: Multiple Modes Of Inhibition Mediated By Biologically Actimentioning

confidence: 99%

Biological targets and mechanisms of action of natural products from marine cyanobacteria

2015

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Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial.

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“…(9). Prodrugs are biologically inactive and require activation through a variety of mechanisms such as hydrolysis, reduction, or rearrangement to render the relevant functional groups for inhibitory activity [90]. The protecting groups usually improve cellular stability of the inhibitor and prevent cellular sequestration or untimely release prior to reaching the site of action.…”

Section: Development Of Modulators Of Histone Acetylationmentioning

confidence: 99%

Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

Salvador¹,

Luesch²

2012

CDT

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Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. This area of research has seen a rapid increase in interest in the past decade, with the structurally diverse natural products-derived compounds at its forefront. These secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.

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Weapons in Disguise—Activating Mechanisms and Protecting Group Chemistry in Nature

Cited by 13 publications

References 85 publications

Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides

Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides

Biological targets and mechanisms of action of natural products from marine cyanobacteria

Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation

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