Antiviral and Anticancer Optimization Studies of the DNA‐binding Marine Natural Product Aaptamine

Bowling, John J.; Pennaka, Hari Kishore; Ivey, K. D.; Wahyuono, Subagus; Kelly, Michelle; Schinazi, Raymond F.; Valeriote, Frederick A.; Graves, David E.; Hamann, Mark T.

doi:10.1111/j.1747-0285.2008.00628.x

Cited by 56 publications

(36 citation statements)

References 37 publications

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“…Several types of activity are known for them including α-adrenoblocking [18], anti-HIV-1 [19], antimicrobial [19], antiherpetic [20], inhibition of monoamine oxidase A [21], inhibition of sortase A [22], and anticancer [19,23]. The mechanism of the antioxidant activity of 1 and 2 was studied for the first time although antioxidant activity had been observed for 1 and 2 previously [7].…”

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confidence: 99%

Antioxidant activityofaromatic alkaloids from the marine sponges Aaptos aaptos and Hyrtios SP.

Utkina

2009

Chem Nat Compd

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547.94+593.4Aaptamine (1) and isoaaptamine (2) were isolated from the marine sponge Aaptos aaptos; 6-bromo- 2′-de-N-methylaplysinopsin (3) from the marine sponge Hyrtios sp. Alkaloids 1-3 were tested for the ability to trap 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, to reduce Folin-Ciocalteau reagent (FCR), and to inhibit oxidation of linoleic acid (LA) induced by peroxide radicals. Compounds 1 (IC 50 18 μM), 2 (IC 50 16 μM), and 3 (IC 50 18 μM) reacted strongly with DPPH, comparable with trolox (IC 50 16 μM) and showed high reducing ability for FCR. The inhibition of LA oxidation by 1-3 was comparable with that of ionol (BHT). It was shown that the antioxidant activity of 1-3 was related to their ability to release both electrons and H atoms.Research on marine natural compounds, which began about 60 years ago, has shown that almost every class of marine organisms synthesizes a variety of molecules with unique structures that are not observed among natural compounds from terrestrial sources owing to the physical and chemical conditions of the marine environment [1,2]. Marine sponges are one of the most ancient classes of animals. The class Demospongiae contains about 95% of living species and is represented around the world by about 14,000-15,000 species [3]. Marine sponges, from which more than 50% of marine natural compounds have been isolated [2], are a rich source of compounds with cytotoxic and antitumor properties [4,5]. The antioxidant activity of compounds isolated from marine sponges is relatively little studied [6-9]. Avarol from the Mediterrean sponge Disydea avara is the only example of a well studied antioxidant from sponges. It is currently manufactured as a preparation against psoriasis [10].In continuation of the search for antioxidants from marine organisms, we investigated marine sponges Aaptos aaptos (Hadromerida, Suberitidae) and Hyrtios sp. (Dictyoceratida, Thorectidae), the alcohol extracts of which acted as strong traps for 2,2-diphenyl-1-picrylhydrazyl radical (DPPH). Our goal was to isolate the active metabolites from these species of marine sponges and study the antioxidant activity and mechanism of antioxidant activity of the obtained compounds.Fractionation of the extract from A. aaptos isolated compounds that were active traps for DPPH. These were aaptamine (1), isoaaptamine (2), and their HCl salts. They were identified by comparison of their spectral properties with the literature [11,12]. Fractionation of the extract from Hyrtios sp. isolated the active compound 6-bromo-2′-de-N-methylaplysinopsin (3), which was identified by comparison of spectral data with those published [13].

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Antioxidant activityofaromatic alkaloids from the marine sponges Aaptos aaptos and Hyrtios SP.

Utkina

2009

Chem Nat Compd

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“…Since their isolation, they attracted a lot of attention due to their unique structures and potent biological activities. They exhibited anti-HIV, anti-fungal, anti-photoaging, anti-infective, anti-fouling, antidepressant, anti-viral, anti-malarial, and cytotoxic activities [13][14][15][16][17][18][19]. Even a bronchodilator drug, benafentrine, has been developed on the basis of benzo[c] [1,6]naphthyridines nucleus and acted as a phosphodiesterase III/IV inhibitor [51].…”

Section: Discussionmentioning

confidence: 99%

Isoaaptamine Induces t-47D Cells Apoptosis and Autophagy via Oxidative Stress

Shih

et al. 2017

65th International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA 2017)

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Abstract:Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer.

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“…Chromenes and 1,6-naphthyridines are associated with a wide spectrum of biological activities [9][10][11]. Consequently, integration of chromene moieties with naphthyridines in a single molecular-framework may increase their biological and fluorescence properties [12].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Microwave-assisted Fe3O4 nanoparticles catalyzed synthesis of chromeno[1,6]naphthyridines in aqueous media

Dandia

Parewa

Gupta

et al. 2015

Catalysis Communications

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Antiviral and Anticancer Optimization Studies of the DNA‐binding Marine Natural Product Aaptamine

Cited by 56 publications

References 37 publications

Antioxidant activityofaromatic alkaloids from the marine sponges Aaptos aaptos and Hyrtios SP.

Antioxidant activityofaromatic alkaloids from the marine sponges Aaptos aaptos and Hyrtios SP.

Isoaaptamine Induces t-47D Cells Apoptosis and Autophagy via Oxidative Stress

Microwave-assisted Fe3O4 nanoparticles catalyzed synthesis of chromeno[1,6]naphthyridines in aqueous media

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