Scabrosin esters and derivatives: chemical derivatization studies and biological evaluation

Chai, Christina L. L.; Elix, John A.; Huleatt, Paul B.; Waring, Paul

doi:10.1016/j.bmc.2004.08.015

Cited by 17 publications

(17 citation statements)

References 21 publications

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“…The spectroscopic data from this material were analogous to an authentic sample obtained commer-cially. Desulfurization of chaetocin using triphenylphosphine under conditions previously described for the synthesis of a scabrosin ester derivative [15] was then attempted. Pleasingly, desulfurization using triphenylphosphine in dichloromethane gave the ring-contracted derivative 2 in good yield (93 %, Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

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On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites

Cherblanc

Gussem

et al. 2011

Chemistry A European J

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Isolation and semisynthetic modification of the fungal metabolite chaetocin gave access to a desulfurized analogue of this natural product. Detailed chiroptical studies, comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to computationally simulated ones, reveal the desulfurization of chaetocin to unambiguously proceed with retention of configuration. Consideration of the plausible mechanisms for this process highlighted inconsistencies in the stereochemical assignment of related molecules in the literature. This in turn allowed the stereochemical reassignment of the natural product analogue dethiodehydrogliotoxin.

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Section: Resultsmentioning

confidence: 99%

“…Far more recent studies would provide a similarly interesting example; the desulfurization of the scabrosin esters (19). [15] Unfortunately, once again, the authors made no attempt to determine the stereochemistry of the product. 1,4-dioxane; *: calcd.…”

mentioning

confidence: 98%

On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites

Cherblanc

Gussem

et al. 2011

Chemistry A European J

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“…To synthesize S-methyl chaetocin, sodium borohydride (1.7 mg, 0.046 mmol) was added to chaetocin (2 mg, 0.0029 mmol) in 75% dichloromethane and 25% methanol at 0°C under dry nitrogen and stirred for 1 hour before addition of excess methyl iodide (3.2 mmol). 20 The solution was stirred for an additional 16 hours and washed with 10% HCl (1 ϫ 0.5 mL), and the organic layer was then extracted with dichloromethane (3 ϫ 1 mL). The organic phases were combined, dried over magnesium sulfate, and evaporated to dryness.…”

Section: Chemical Modifications Of Chaetocinmentioning

confidence: 99%

Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress

Isham

Tibodeau²,

Jin³

et al. 2006

Blood

175

109

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Chaetocin, a thiodioxopiperazine natural product previously unreported to have anticancer effects, was found to have potent antimyeloma activity in IL-6-dependent and -independent myeloma cell lines in freshly collected sorted and unsorted patient CD138(+) myeloma cells and in vivo. Chaetocin largely spares matched normal CD138(-) patient bone marrow leukocytes, normal B cells, and neoplastic B-CLL (chronic lymphocytic leukemia) cells, indicating a high degree of selectivity even in closely lineage-related B cells. Furthermore, chaetocin displays superior ex vivo antimyeloma activity and selectivity than doxorubicin and dexamethasone, and dexamethasone- or doxorubicin-resistant myeloma cell lines are largely non-cross-resistant to chaetocin. Mechanistically, chaetocin is dramatically accumulated in cancer cells via a process inhibited by glutathione and requiring intact/unreduced disulfides for uptake. Once inside the cell, its anticancer activity appears mediated primarily through the imposition of oxidative stress and consequent apoptosis induction. Moreover, the selective antimyeloma effects of chaetocin appear not to reflect differential intracellular accumulation of chaetocin but, instead, heightened sensitivity of myeloma cells to the cytotoxic effects of imposed oxidative stress. Considered collectively, chaetocin appears to represent a promising agent for further study as a potential antimyeloma therapeutic.

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“…1a–b Indeed, the chemical ablation of the sulfur bridge in naturally occurring alkaloids ( e.g ., chaetocin A ( 4 ), 13f gliotoxin ( 1 ) 15 , sporidesmin 16 ) or the synthesis of analogs devoid of sulfur at the α-positions of the cyclo -dipeptide 17a results in biologically inactive compounds. Similarly, reductive S -methylation of the epidithiodiketopiperazine motif in a number of natural products ( e.g ., gliotoxin ( 1 ), 1b,5c,n,8a chaetocin A ( 4 ), 18 scabrosin, 19 sporidesmin, 16,20 T988 B, 21 bionectin C ( 8 ), 4 and chetracin D 22 ) unfailingly results in a dramatic loss of biological activity. Furthermore, a general pattern between the degree of sulfuration and the intensity of the biological response has not been clearly established.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, epimonothiodiketopiperazine metabolites have been reported to be at least one order of magnitude less active than their congeners. 1b,19,24,25 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

et al. 2013

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The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure–activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo.

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Scabrosin esters and derivatives: chemical derivatization studies and biological evaluation

Cited by 17 publications

References 21 publications

On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites

On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites

Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress

Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

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