Total Synthesis and Stereochemical Assignment of Burkholdac B, a Depsipeptide HDAC Inhibitor

Benelkebir, Hanae; Donlevy, Alison M.; Packham, Graham; Ganesan, A.

doi:10.1021/ol202197q

Cited by 34 publications

(26 citation statements)

References 52 publications

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“…4 While this manuscript was in preparation, Ganesan and co-workers reported the first total synthesis of burkholdac B and corrected the originally misassigned structure. 5 The stereochemical revision of burkholdac B is identical with that described in the current manuscript. Here we wish to describe the total synthesis and revised stereochemical assignment of burkholdac A.…”

supporting

confidence: 52%

Total Synthesis and Stereochemical Revision of Burkholdac A

Liu¹,

Ma²,

Liu³

et al. 2012

Synlett

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supporting

confidence: 52%

Total Synthesis and Stereochemical Revision of Burkholdac A

Liu¹,

Ma²,

Liu³

et al. 2012

Synlett

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“…A recent report of the independently discovered burkholdac B, shown to be identical to TDP-A, had potent picomolar growth inhibitory activity in MCF7 breast cancer cells [25]. These in vitro results of burkholdac B were not consistent with the results of TDP-A published by the Cheng group [12].…”

Section: Discussionmentioning

confidence: 76%

Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy

Wilson

Khabele

2012

J Ovarian Res

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BackgroundNew treatment strategies are emerging to target DNA damage response pathways in ovarian cancer. Our group has previously shown that the class I biased HDAC inhibitor romidepsin (FK228) induces DNA damage response and has potent cytotoxic effects in ovarian cancer cells. Here, we investigated newly discovered HDAC inhibitors, thailandepsin A (TDP-A) and thailandepsin B (TDP-B), to determine the effects on cell viability, apoptosis and DNA damage response in ovarian cancer cells.MethodsFK228, TDP-A and TDP-B were tested in five ovarian cancer cell lines. Cellular viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Immunofluorescence assays were used to assess activated caspase 3. Western blots were performed to detect protein expression of PARP cleavage, pH2AX, P-glycoprotein and tubulin acetylation.ResultsTreatment with TDPs decreased cell viability at nanonomolar concentrations in four of the five ovarian cancer cell lines studied. Similar to FK228, both TDP compounds exerted minimal effects on NCI/ADR-RES ovarian cancer cells. Across the four cell lines sensitive to the TDPs, TDP-B consistently had a greater inhibitory effect than TDP-A on cell viability. TDP-B also had relatively greater effects on promoting cell apoptosis and induction of pH2AX (a mark of DNA damage response), than TDP-A. These antitumor effects of TDP-B were of similar magnitude to those induced by an equal concentration of FK228. Similar to FK228, the nanomolar concentrations of the TDPs had little effect on tubulin acetylation (a mark of class II HDAC6 inhibition).ConclusionsThe new small molecule HDAC inhibitors TDP-A and TDP-B are FK228 analogues that suppress cell viability and induce apoptosis at nanomolar drug concentrations. TDP-B showed the most similarity to the biological activity of FK228 with greater cytotoxic effects than TDP-A in vitro. Our results indicate that FK228-like small molecule class I HDAC-biased HDAC inhibitors have therapeutic potential for ovarian cancer.

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“…On the other hand, only moderate inhibition of class IIb HDAC enzymes has been recorded (Table ) . Furthermore, the oxidized disulfide “prodrugs” show cytotoxic activity towards a number of cancer cell lines . The potential of the sulfur‐containing macrocyclic HDAC inhibitors is exemplified by romidepsin ( 5 ), which is approved by the FDA for treatment of cutaneous T‐cell lymphoma and peripheral T‐cell lymphoma …”

Section: Naturally Occurring Macrocyclic Hdac Inhibitorsmentioning

confidence: 99%

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

et al. 2016

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Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen. Nevertheless, it has been speculated that using macrocyclic compounds to target HDAC enzymes might hold an advantage over the use of traditional hydroxamic‐acid‐containing inhibitors, which rely on chelation to the conserved active‐site zinc ion. Here we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and on structure–activity relationship studies inspired by these molecules, as well as on efforts aimed at fully synthetic macrocyclic HDAC inhibitors.

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Total Synthesis and Stereochemical Assignment of Burkholdac B, a Depsipeptide HDAC Inhibitor

Cited by 34 publications

References 52 publications

Total Synthesis and Stereochemical Revision of Burkholdac A

Total Synthesis and Stereochemical Revision of Burkholdac A

Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

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