Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1α/p300 Interaction

Abstract

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.

New Discorhabdin B Dimers with Anticancer Activity from the Antarctic Deep-Sea Sponge Latrunculia biformis

“…The carbonyl signals belonging to C-11 and C-11' did not appear in the NMR spectra, which is a common case in many pyrroloiminoquinone alkaloids [11,12,14]. Our attempts to locate the two carbonyl carbons by using a high-resolution cryo NMR probe were unsuccessful, however, the structural homology was obvious based on the HRMS, 1D, and 2D NMR data and the comparison of the data with related compounds in the literature [18,19]. Figure S19).…”

“…So far, only five natural discorhabdin dimers ((+)-discorhabdin W, (−)-discorhabdin W, (+)-16a,17a-dehydrodiscorhabdin W, (−)-16a,17a-dehydrodiscorhabdin W, and (−)-28,29-dihydrodiscorhabdin B dimer) that are linked to each other with a sulfide or disulfide bond have been reported and all derive from Latrunculia sp. collected from New Zealand or Australia [11,17,18]. In addition, the discorhabdin B dimer has been reported as an artifact that formed after the storage of discorhabdin B [19].…”

Antiangiogenic Activity of Coptis chinensis Franch. Water Extract in in vitro and ex vivo Angiogenesis Models

“…It has been demonstrated that antiangiogenic drugs that target molecules within the angiogenic signaling pathway inhibit the tumor growth [46]. Recently, more efforts have been focused on the discovery of novel, non-cytotoxic, antiangiogenic compounds or natural product extracts, some of which have been used clinically for thousands of years as important alternative remedies for a wide variety of diseases, including cancer [16,32,33,36].…”

The colourful chemistry of South African latrunculid sponges

“…28,36,37 In addition to whole cell screens, the bioactivity of marine pyrroloiminoquinones against medicinally relevant enzyme targets is also of interest. 28,38,39 The isolation of a large cohort of pyrroloiminoquinone metabolites from four species of South African latrunculid sponges provided a unique opportunity to explore the cytotoxicity (Tables 2 and 3) and structure activity relationship of 20 of these compounds against a human colon tumour cell line (HCT-116). 12 Discorhabdin A, with an IC 50 of 7 nM, was the most active compound against this cancer cell line.…”