Marine Drugs

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637 KiB

Open AccessArticle

Modification of Marine Natural Product Ningalin B and SAR Study Lead to Potent P-Glycoprotein Inhibitors

by Chao Yang, Iris L. K. Wong, Wen Bin Jin, Tao Jiang, Larry M. C. Chow and Sheng Biao Wan

Mar. Drugs 2014, 12(10), 5209-5221; https://doi.org/10.3390/md12105209 - 17 Oct 2014

Cited by 13 | Viewed by 8233

Abstract

In this study, new marine ningalin B analogues containing a piperazine or a benzoloxy group at ring C have been synthesized and evaluated on their P-gp modulating activity in human breast cancer and leukemia cell lines. Their structure-activity relationship was preliminarily studied. Compounds [...] Read more.

In this study, new marine ningalin B analogues containing a piperazine or a benzoloxy group at ring C have been synthesized and evaluated on their P-gp modulating activity in human breast cancer and leukemia cell lines. Their structure-activity relationship was preliminarily studied. Compounds 19 and 20 are potent P-gp inhibitors. These two synthetic analogues of permethyl ningalin B may be potentially used as effective modulators of P-gp-mediated drug resistance in cancer cells. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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834 KiB

Open AccessArticle

Chronic Toxicity Study of Neosaxitoxin in Rats

by Ramiro J. Zepeda, Manila Candiracci, Nicolas Lobos, Sebastian Lux and Hugo F. Miranda

Mar. Drugs 2014, 12(9), 5055-5071; https://doi.org/10.3390/md12095055 - 25 Sep 2014

Cited by 9 | Viewed by 7850

Abstract

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated [...] Read more.

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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589 KiB

Open AccessCommunication

Tricyclic Guanidine Alkaloids from the Marine Sponge Acanthella cavernosa that Stabilize the Tumor Suppressor PDCD4

by Tanja Grkovic, Johanna S. Blees, Magdalena M. Bayer, Nancy H. Colburn, Cheryl L. Thomas, Curtis J. Henrich, Megan L. Peach, James B. McMahon, Tobias Schmid and Kirk R. Gustafson

Mar. Drugs 2014, 12(8), 4593-4601; https://doi.org/10.3390/md12084593 - 21 Aug 2014

Cited by 17 | Viewed by 6997

Abstract

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G ( [...] Read more.

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC₅₀ values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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870 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity

by Alessandra Mirtes Marques Neves Gonçalves, Aline Brito De Lima, Maria Cristina Da Silva Barbosa, Luiz Fernando De Camargos, Júlia Teixeira De Oliveira, Camila De Souza Barbosa, José Augusto Ferreira Perez Villar, André Carvalho Costa, Isabella Viana Gomes da Silva, Luciana Maria Silva, Fernando De Pilla Varotti, Fabio Vieira Dos Santos and Gustavo Henrique Ribeiro Viana

Mar. Drugs 2014, 12(8), 4361-4378; https://doi.org/10.3390/md12084361 - 31 Jul 2014

Cited by 18 | Viewed by 7182

Abstract

Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action [...] Read more.

Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action against tumoral cell lines. Here, we describe the synthesis and anticancer activity of eight new 3-alkylpyridine alkaloid (3-APA) analogs in four steps and with good yields. The key step for the synthesis of these compounds is a Williamson etherification under phase-transfer conditions. We investigated the influence of the length of the alkyl chain attached to position 3 of the pyridine ring on the cytotoxicity of these compounds. Biological assays demonstrated that compounds with an alkyl chain of ten carbon atoms (4c and 5c) were the most active against two tumoral cell lines: RKO-AS-45-1 and HeLa. Micronucleus and TUNEL assays showed that both compounds are mutagenic and induce apoptosis. In addition, Compound 5c altered the cellular actin cytoskeleton in RKO-AS-45-1 cells. The results suggest that Compounds 4c and 5c may be novel prototype anticancer agents. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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744 KiB

Open AccessArticle

Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels

by Steve Peigneur, Aleš Žula, Nace Zidar, Fiona Chan-Porter, Robert Kirby, David Madge, Janez Ilaš, Danijel Kikelj and Jan Tytgat

Mar. Drugs 2014, 12(4), 2132-2143; https://doi.org/10.3390/md12042132 - 4 Apr 2014

Cited by 9 | Viewed by 6859

Abstract

Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (Na_V) channels. Since there is an urgent need for small molecule Na_V channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin [...] Read more.

Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (Na_V) channels. Since there is an urgent need for small molecule Na_V channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and Na_V channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of Na_V channel isoforms, both in voltage clamp and patch clamp conditions. Even though clathrodin was not found to exert any activity, some analogues were capable of modulating the Na_V channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based Na_V channel modulators. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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237 KiB

Open AccessArticle

Two New Tryptamine Derivatives, Leptoclinidamide and (-)-Leptoclinidamine B, from an Indonesian Ascidian Leptoclinides dubius

by Hiroyuki Yamazaki, Defny S. Wewengkang, Teruaki Nishikawa, Henki Rotinsulu, Remy E. P. Mangindaan and Michio Namikoshi

Mar. Drugs 2012, 10(2), 349-357; https://doi.org/10.3390/md10020349 - 10 Feb 2012

Cited by 12 | Viewed by 7875

Abstract

Two new tryptamine-derived alkaloids, named as leptoclinidamide (1) and (-)-leptoclinidamine B (2), were isolated from an Indonesian ascidian Leptoclinides dubius together with C²-α-D-mannosylpyranosyl-L-tryptophan (3). The structure of 1 was assigned on the basis of spectroscopic [...] Read more.

Two new tryptamine-derived alkaloids, named as leptoclinidamide (1) and (-)-leptoclinidamine B (2), were isolated from an Indonesian ascidian Leptoclinides dubius together with C²-α-D-mannosylpyranosyl-L-tryptophan (3). The structure of 1 was assigned on the basis of spectroscopic data for 1 and its N-acetyl derivative (4). Compound 1 was an amide of tryptamine with two β-alanine units. Although the planar structure of 2 is identical to that of the known compound (+)-leptoclinidamine B (5), compound 2 was determined to be the enantiomer of 5 based on amino acid analysis using HPLC methods. Compounds 1 to 4 were evaluated for cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells, but none of the compounds showed activity. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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1277 KiB

Open AccessArticle

Expression, Purification and Bioactivities Analysis of Recombinant Active Peptide from Shark Liver

by Zhengbing Lv, Yu Ou, Qian Li, Wenping Zhang, Boping Ye and Wutong Wu

Mar. Drugs 2009, 7(2), 258-267; https://doi.org/10.3390/md7020258 - 22 Jun 2009

Cited by 13 | Viewed by 10607

Abstract

The Active Peptide from Shark Liver (APSL) was expressed in E. coli BL21 cells. The cDNA encoding APSL protein was obtained from shark regenerated hepatic tissue by RT-PCR, then it was cloned in the pET-28a expression vector. The expressed fusion protein was purified [...] Read more.

The Active Peptide from Shark Liver (APSL) was expressed in E. coli BL21 cells. The cDNA encoding APSL protein was obtained from shark regenerated hepatic tissue by RT-PCR, then it was cloned in the pET-28a expression vector. The expressed fusion protein was purified by Ni-IDA affinity chromatography. SDS-PAGE and HPLC analysis showed the purity of the purified fusion protein was more than 98%. The recombinant APSL (rAPSL) was tested for its biological activity both in vitro, by its ability to improve the proliferation of SMMC7721 cells, and in vivo, by its significant protective effects against acute hepatic injury induced by CCl₄ and AAP (acetaminophen) in mice. In addition, the rAPSL could decrease the blood glucose concentration of mice with diabetes mellitus induced by alloxan. Paraffin sections of mouse pancreas tissues showed that rAPSL (3 mg/kg) could effectively protect mouse islets from lesions induced by alloxan, which indicated its potential application in theoretical research and industry. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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Review

Jump to: Research

415 KiB

Open AccessReview

New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds

by Amir E. Wahba and Mark T. Hamann

Mar. Drugs 2010, 8(8), 2395-2416; https://doi.org/10.3390/md8082395 - 24 Aug 2010

Cited by 23 | Viewed by 11965

Abstract

There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative [...] Read more.

There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and g-lactams. In addition, progress on the synthesis of b-carboline (manzamine) alkaloids will also be discussed. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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380 KiB

Open AccessReview

Neurotoxic Alkaloids: Saxitoxin and Its Analogs

by Maria Wiese, Paul M. D’Agostino, Troco K. Mihali, Michelle C. Moffitt and Brett A. Neilan

Mar. Drugs 2010, 8(7), 2185-2211; https://doi.org/10.3390/md8072185 - 20 Jul 2010

Cited by 630 | Viewed by 37013

Abstract

Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria [...] Read more.

Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs—each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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349 KiB

Open AccessReview

Alkaloids in Marine Algae

by Kasım Cemal Güven, Aline Percot and Ekrem Sezik

Mar. Drugs 2010, 8(2), 269-284; https://doi.org/10.3390/md8020269 - 4 Feb 2010

Cited by 171 | Viewed by 22782

Abstract

This paper presents the alkaloids found in green, brown and red marine algae. Algal chemistry has interested many researchers in order to develop new drugs, as algae include compounds with functional groups which are characteristic from this particular source. Among these compounds, alkaloids [...] Read more.

This paper presents the alkaloids found in green, brown and red marine algae. Algal chemistry has interested many researchers in order to develop new drugs, as algae include compounds with functional groups which are characteristic from this particular source. Among these compounds, alkaloids present special interest because of their pharmacological activities. Alkaloid chemistry has been widely studied in terrestrial plants, but the number of studies in algae is insignificant. In this review, a detailed account of macro algae alkaloids with their structure and pharmacological activities is presented. The alkaloids found in marine algae may be divided into three groups: 1. Phenylethylamine alkaloids, 2. Indole and halogenated indole alkaloids, 3. Other alkaloids. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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175 KiB

Open AccessReview

Terpenyl-Purines from the Sea

by Marina Gordaliza

Mar. Drugs 2009, 7(4), 833-849; https://doi.org/10.3390/md7040833 - 23 Dec 2009

Cited by 39 | Viewed by 15212

Abstract

Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp., Raspailia sp.). Some agelasine analogs and related structures have displayed high general toxicity towards protozoa, and have exhibited broad-spectrum antimicrobial activity [...] Read more.

Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp., Raspailia sp.). Some agelasine analogs and related structures have displayed high general toxicity towards protozoa, and have exhibited broad-spectrum antimicrobial activity against a variety of species, including Mycobacterium tuberculosis, and also an important cytotoxic activity against several cancer cell lines, including multidrug-resistant ones. Of particular interest in this context are the asmarines (tetrahydro[1,4]diazepino[1,2,3-g,h]purines), which have shown potent antiproliferative activity against several types of human cancer cell lines. This review summarizes the sources of isolation, chemistry and bioactivity of marine alkylpurines and their bioactive derivatives. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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955 KiB

Open AccessReview

Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

by Sébastien Deslandes, Stefan Chassaing and Evelyne Delfourne

Mar. Drugs 2009, 7(4), 754-786; https://doi.org/10.3390/md7040754 - 1 Dec 2009

Cited by 43 | Viewed by 14016

Abstract

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial [...] Read more.

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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