Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models

Em, Harris; Strope, Jonathan D.; Sl, Beedie; Pa, Huang; Goey, Andrew K.L.; Cook, Kristina M.; Cj, Schofield; Ch, Chau; Cadelis, Melissa M.; Copp, Brent R.; Kr, Gustafson; Figg, William D.

doi:10.3390/md16070241

Cited by 26 publications

(24 citation statements)

References 15 publications

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“…There are several ongoing efforts, including our own, to develop HIF inhibitors for cancer treatment. Many of the drugs are aimed at blocking the HIF-1α or HIF-2α subunit from binding to partners such as p300 [ 173 , 174 , 175 , 176 , 177 , 178 , 179 ], HIF-1β [ 180 , 181 , 182 , 183 , 184 , 185 ], HSP90 [ 186 , 187 ] or binding to the DNA itself [ 188 ]. p300 also binds to the CLOCK/BMAL1 heterodimer [ 189 ] and p300 inhibitors used to target HIF may also target circadian regulation.…”

Section: Restoring the Circadian Clock In Tumor Cells May Be An Efmentioning

confidence: 99%

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

et al. 2019

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Circadian rhythms regulate many physiological and behavioral processes, including sleep, metabolism and cell division, which have a 24-h oscillation pattern. Rhythmicity is generated by a transcriptional–translational feedback loop in individual cells, which are synchronized by the central pacemaker in the brain and external cues. Epidemiological and clinical studies indicate that disruption of these rhythms can increase both tumorigenesis and cancer progression. Environmental changes (shift work, jet lag, exposure to light at night), mutations in circadian regulating genes, and changes to clock gene expression are recognized forms of disruption and are associated with cancer risk and/or cancer progression. Experimental data in animals and cell cultures further supports the role of the cellular circadian clock in coordinating cell division and DNA repair, and disrupted cellular clocks accelerate cancer cell growth. This review will summarize studies linking circadian disruption to cancer biology and explore how such disruptions may be further altered by common characteristics of tumors including hypoxia and acidosis. We will highlight how circadian rhythms might be exploited for cancer drug development, including how delivery of current chemotherapies may be enhanced using chronotherapy. Understanding the role of circadian rhythms in carcinogenesis and tumor progression will enable us to better understand causes of cancer and how to treat them.

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Section: Restoring the Circadian Clock In Tumor Cells May Be An Efmentioning

confidence: 99%

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

et al. 2019

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“…In many cases, discorhabdin alkaloids have been reported to exhibit cytotoxicity towards tumour cell lines [ 1 , 2 , 3 , 4 , 6 , 8 , 9 ], with additional biological activities also including inhibition of protein–protein interaction associated with hypoxia-inducible factor 1α and its transcriptional coactivator p300 [ 10 , 11 ], antibacterial [ 12 , 13 , 14 ] and antimalarial [ 13 ] properties. The biological activities of simple dienone-containing examples of the discorhabdins has been attributed to the electrophilic properties of this moiety [ 2 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

2020

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The cytotoxic marine natural product discorhabdin C contains a 2,6-dibromo-cyclohexa-2,5-diene moiety, previously proposed to be a critical feature required for biological activity. We have determined that the dienone-ring of discorhabdin C is indeed electrophilic, reacting with thiol and amine nucleophiles, affording debrominated adducts. In the case of reaction with 1-aminopentane the product contains an unusual C-2/N-18 ring closed, double-hydrate moiety. This electrophilic reactivity also extends to proteins, with lysozyme-discorhabdin C adducts being detected by ESI mass spectrometry. These results prompted further examination of an extract of discorhabdin C-producing sponge, Latrunculia (Latrunculia) trivetricillata, leading to the isolation and characterisation of a new example of a C-1/N-13 linked discorhabdin dimer that shared structural similarities with the 1-aminopentane-discorhabdin C adduct. To definitively assess the influence of the dienone moiety of discorhabdin C on cytotoxicity, a semi-synthetic hydrogenation derivative was prepared, affording a didebrominated ring-closed carbinolamine that was essentially devoid of tumour cell line cytotoxicity. Antiparasitic activity was assessed for a set of 14 discorhabdin alkaloids composed of natural products and semi-synthetic derivatives. Three compounds, (-)-discorhabdin L, a dimer of discorhabdin B and the discorhabdin C hydrogenation carbinolamine, exhibited pronounced activity towards Plasmodium falciparum K1 (IC50 30–90 nM) with acceptable to excellent selectivity (selectivity index 19–510) versus a non-malignant cell line.

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“…Recently, pyrroloiminoquinones have attracted a surge of renewed interest as potential anticancer drug leads. Several makaluvamines, discorhabdins, and synthetic analogs have shown promising results in anticancer assays [3,4,15,16] and as inhibitors of the formation of the cancer-related HIF-1α/p300 enzyme complex [17].…”

Section: Introductionmentioning

confidence: 99%

Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges

et al. 2019

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The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.

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Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models

Cited by 26 publications

References 15 publications

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges

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