Polyprenyl-hydroquinones and -furans from three marine sponges inhibit the cell cycle regulating phosphatase CDC25A

Abstract

The CDC25 phosphatases regulate the cell division cycle by controlling the activity of cyclin-dependent kinases. While screening for inhibitors of phosphatases among natural products we repeatedly found that some polyprenyl-hydroquinones and polyprenyl-furans (furanoterpenoids) (furospongins, furospinosulins) were potent CDC25 phosphatase inhibitors. These compounds were extracted, isolated and identified independently from three sponge species (Spongia officinalis, Ircinia spinulosa, Ircinia muscarum), collected at different locations in the Mediterranean Sea. The compounds were inactive on the Ser/Thr phosphatase PP2C-alpha and on three kinases (CDK1, CDK5, GSK-3), suggesting that some potent and selective CDC25 phosphatase might be designed from these initial structures.

Natural Compounds as Modulators of Cell Cycle Arrest: Application for Anticancer Chemotherapies

“…Natural compounds (polyprenyl-hydroquinones and polyprenyl-furans [furanoterpenoids, furospongins, furospinosulins]) were isolated from sponge species Spongia officinalis, Ircinia spinulosa, and Ircinia muscarum , collected at different locations in the Mediterranean Sea, as described in [246]. They were shown exhibit potent CDC25 phosphatase inhibitor activities [246]. Aqueous extract of Phyllanthus amarus inhibited a growth of 20-methylcholanthrene-induced sarcoma in mice [247].…”

Natural products as a source of Alzheimer's drug leads

“…No details have been reported after the initial patent though. Interestingly, a related difuran analog 306 was inactive against both GSK3 and CDK5, suggesting the furanone moiety is crucial for activity.…”

Furospinosulin‐1, Marine Spongean Furanosesterterpene, Suppresses the Growth of Hypoxia‐Adapted Cancer Cells by Binding to Transcriptional Regulators p54nrb and LEDGF/p75

“…Tasdemir et al . reported that 1 showed weak anti‐proliferative activity against isogenic human colon cancer HCT‐116 cells under normoxic conditions, and Erdogan‐Orhan et al . reported that 1 inhibited CDC25A (cell division cycle 25 homologue A phosphatase), which regulates the cell cycle.…”

“…[9,10] The furanosesterterpenef urospinosulin-1 (1)w as originally isolated from the marine sponge Ircinia spinosula. [11] Ta sdemir et al [12] reported that 1 showedw eak anti-proliferative activity against isogenic human colon cancerH CT-116 cells under normoxic conditions, and Erdogan-Orhan et al [13] reported that 1 inhibited CDC25A (cell division cycle 25 homologue Ap hos-Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer.C ancer research has therefore focused on the identification of molecules responsible for hypoxiaa daptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells. The marine natural product furospinosulin-1 (1) has displayed hypoxia-selectiveg rowth inhibition against cul-tured cancerc ells, and has shown in vivo anti-tumor activity, althoughi ts precise mode of action and molecular targets remain unclear.I nt his study,w ef ound that 1 is selectively effective against hypoxic regions of tumors, and that it directly binds to the transcriptional regulators p54 nrb andL EDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells.…”