Aaptamine

J Proteomics. 2014 Jan 16;96:223-39.

Activity of aaptamine and two derivatives, demethyloxyaaptamine and isoaaptamine, in cisplatin-resistant germ cell cancer.[Pubmed: 24269226 ]

We analyzed the effects of all three marine alkaloids Aaptamine, demethyloxyAaptamine and isoAaptamine in NT2-R, a cisplatin-resistant subline of the human embryonal carcinoma cell line NT2.
METHODS AND RESULTS:
All Aaptamines were found to be equally effective in both cell lines, excluding cross-resistance between Aaptamines and cisplatin in vitro. At the inhibitory concentration (IC50), Aaptamine exerted an antiproliferative effect, whereas demethyloxyAaptamine and isoAaptamine were strong inducers of apoptosis. We analyzed the changes in the proteome of NT2-R cells treated with these compounds. 16-22 proteins were found to be significantly altered, of which several were validated by Western blotting and two-dimensional Western blotting analysis. Changes in the proteome pattern frequently resulted from post-transcriptional protein modifications, i.e. phosphorylation or hypusination in the case of eIF5A. Although the lists of altered proteins were heterogeneous and compound-specific, gene ontology analyses identified rather similar profiles regarding the affected molecular functions. Ingenuity pathway analysis by IPA put the following factors in a central position of the hypothetical networks: myc and p53 for Aaptamine; tumor necrosis factor (TNF) for demethyloxyAaptamine; and all three, myc, p53, and TNF for isoAaptamine.
CONCLUSIONS:
Our results represent an important step towards a better understanding of the molecular basis underlying the observed bioactivity of these promising marine compounds.

J Pharm Pharmacol. 1984 Nov;36(11):785-6.

Alpha-adrenoceptor blocking action of aaptamine, a novel marine natural product, in vascular smooth muscle.[Pubmed: 6150989]

METHODS AND RESULTS:
In the rabbit isolated aorta and renal artery, Aaptamine (3 X 10(-5)M), a novel heteroaromatic substance isolated from a sea sponge Aaptos aaptos produced a parallel, rightward shift of the dose-response curve for noradrenaline, whereas that for histamine or KCl was not affected. But, the derivatives of Aaptamine, demethylAaptamine, demethyloxyAaptamine, dihydroAaptamine and dihydrodemethylAaptamine at concentrations of 10(-5) to 10(-4)M had no effect on the dose-response curve for noradrenaline.
CONCLUSIONS:
These results suggest that Aaptamine is a competitive antagonist of alpha-adrenoceptors in vascular smooth muscles.

J Asian Nat Prod Res. 2014 Dec;16(12):1139-47.

Anti-photoaging effect of aaptamine in UVB-irradiated human dermal fibroblasts and epidermal keratinocytes.[Pubmed: 25465718 ]

Chronic exposure to ultraviolet (UV) irradiation causes sunburn, inflammatory responses, skin cancer, and photoaging. Photoaging, in particular, generates reactive oxygen species (ROS) that stimulate mitogen-activated protein kinase (MAPK) signaling and transcription factors. UV irradiation also activates matrix metalloproteinases (MMPs) expression and inactivates collagen synthesis. Aaptamine, a marine alkaloid isolated from the marine sponge, has been reported to have antitumor, antimicrobial, antiviral, and antioxidant activities. However, the photo-protective effects of Aaptamine have not been elucidated.
METHODS AND RESULTS:
In this study, our data demonstrated that Aaptamine deactivated UVB-induced MAPK and activator protein-1 signaling by suppressing ROS, resulting in attenuating the expression of MMPs in UVB-irradiated human dermal fibroblasts. Aaptamine also decreased proinflammatory cytokines such as cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and nuclear factor-kappa B subunits in UVB-irradiated human keratinocytes.
CONCLUSIONS:
In conclusion, we suggest that Aaptamine represents a novel and effective strategy for treatment and prevention of photoaging.

Biochem Biophys Res Commun. 2006 Mar 31;342(1):101-6.

Aaptamine, a spongean alkaloid, activates p21 promoter in a p53-independent manner.[Pubmed: 16480688 ]

METHODS AND RESULTS:
Aaptamine, a benzonaphthyridine alkaloid was isolated from a marine sponge on the guidance of a bioassay using the transfected human osteosarcoma MG63 cells (MG63luc(+)). Aaptamine activated p21 promoter stably transfected in MG63 cells dose-dependently at the concentrations of 20-50microM. Expression of p21 and its mRNA in the wild-type MG63 cells also increased by Aaptamine-treatment. Furthermore, the cell cycle of MG63 cells was arrested at the G2/M phase within 48h by the Aaptamine-treatment. To analyze a responsive element of p21 promoter in the up-regulation of p21 by Aaptamine, MG63 cells were transiently transfected with a series of the deleted or mutated promoter segments, and induction of luciferase with Aaptamine treatment was examined by using these corresponding transfected cells.
CONCLUSIONS:
The activation of p21 promoter by Aaptamine was led through acting Sp1 sites between -82 and -50bp in a p53-independent manner.

Bioorg Med Chem Lett. 2010 Jun 1;20(11):3341-3.

Aaptamine, an alkaloid from the sponge Aaptos suberitoides, functions as a proteasome inhibitor[Pubmed: 20451377 ]

METHODS AND RESULTS:
Aaptamine (1), isoAaptamine (2), and demethylAaptamine (3) were isolated from the marine sponge Aaptossuberitoides collected in Indonesia as inhibitors of the proteasome. They inhibited the chymotrypsin-like and caspase-like activities of the proteasome with IC(50) values of 1.6-4.6 microg/mL, while they showed less inhibition of the trypsin-like activity of the proteasome.
CONCLUSIONS:
The three compounds showed cytotoxic activities against HeLa cells, but their cytotoxicity did not correlate with their potency as proteasome inhibitors, strongly suggesting that their proteasomal inhibitory activity is dispensable to their cytotoxicity.

Chem Biol Drug Des. 2008 Mar;71(3):205-15.

Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine.[Pubmed: 18251774]

Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity.
METHODS AND RESULTS:
Based on UV-vis absorbance titration data, the K(obs) for Aaptamine was 4.0 (+/-0.2) x 10(3) which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known Aaptamine analogs and vary its absorption characteristics. Overall, 26 Aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoAaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay.
CONCLUSIONS:
Details of Aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.