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Special Issue "Alkaloid Analogs"

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (30 April 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Sadanandan E. Velu

Department of Chemistry, CHEM-280, The University of Alabama at Birmingham 901, 14th Street South, Birmingham, AL 35294-1240, USA
Website | E-Mail
Phone: (205) 975 2478
Fax: +1 205 934 2543
Interests: bioactive marine alkaloids; analogues; synthesis; anti-cancer; anti-infective; enzyme inhibitors; structure based drug design; fragment based drug design; in silico virtual screening; SAR studies; lead optimization

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs).

Keywords

  • marine alkaloid
  • analog
  • synthesis
  • cytotoxic
  • anticancer
  • anti-inflammatory
  • antibacterial
  • antimalarial
  • antiviral
  • Indole
  • Imidazole
  • pyrrole
  • carboline
  • quinoline
  • isoquinoline
  • carbazole
  • pyrroloquinoline
  • quinone
  • pyrroloquinone
  • pyrroloiminoquinone

Published Papers (12 papers)

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Research

Jump to: Review

Open AccessArticle Modification of Marine Natural Product Ningalin B and SAR Study Lead to Potent P-Glycoprotein Inhibitors
Mar. Drugs 2014, 12(10), 5209-5221; doi:10.3390/md12105209
Received: 11 March 2014 / Revised: 1 September 2014 / Accepted: 25 September 2014 / Published: 17 October 2014
Cited by 5 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
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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Open AccessArticle Chronic Toxicity Study of Neosaxitoxin in Rats
Mar. Drugs 2014, 12(9), 5055-5071; doi:10.3390/md12095055
Received: 29 January 2014 / Revised: 6 June 2014 / Accepted: 7 July 2014 / Published: 25 September 2014
Cited by 2 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text
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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Open AccessCommunication Tricyclic Guanidine Alkaloids from the Marine Sponge Acanthella cavernosa that Stabilize the Tumor Suppressor PDCD4
Mar. Drugs 2014, 12(8), 4593-4601; doi:10.3390/md12084593
Received: 4 June 2014 / Revised: 25 June 2014 / Accepted: 24 July 2014 / Published: 21 August 2014
Cited by 4 | PDF Full-text (589 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessArticle Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity
Mar. Drugs 2014, 12(8), 4361-4378; doi:10.3390/md12084361
Received: 24 April 2014 / Revised: 24 June 2014 / Accepted: 9 July 2014 / Published: 31 July 2014
Cited by 2 | PDF Full-text (870 KB) | HTML Full-text | XML Full-text
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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Open AccessArticle Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels
Mar. Drugs 2014, 12(4), 2132-2143; doi:10.3390/md12042132
Received: 3 January 2014 / Revised: 21 February 2014 / Accepted: 25 March 2014 / Published: 4 April 2014
Cited by 4 | PDF Full-text (744 KB) | HTML Full-text | XML Full-text
Abstract
Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (NaV) channels. Since there is an urgent need for small molecule NaV 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 (NaV) channels. Since there is an urgent need for small molecule NaV channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and NaV channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of NaV 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 NaV channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based NaV channel modulators. Full article
(This article belongs to the Special Issue Alkaloid Analogs)
Open AccessArticle Two New Tryptamine Derivatives, Leptoclinidamide and (-)-Leptoclinidamine B, from an Indonesian Ascidian Leptoclinides dubius
Mar. Drugs 2012, 10(2), 349-357; doi:10.3390/md10020349
Received: 27 December 2011 / Revised: 23 January 2012 / Accepted: 7 February 2012 / Published: 10 February 2012
Cited by 3 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
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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Open AccessArticle Expression, Purification and Bioactivities Analysis of Recombinant Active Peptide from Shark Liver
Mar. Drugs 2009, 7(2), 258-267; doi:10.3390/md7020258
Received: 20 April 2009 / Revised: 13 June 2009 / Accepted: 13 June 2009 / Published: 22 June 2009
Cited by 5 | PDF Full-text (1277 KB) | HTML Full-text | XML Full-text
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)

Review

Jump to: Research

Open AccessReview New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds
Mar. Drugs 2010, 8(8), 2395-2416; doi:10.3390/md8082395
Received: 26 July 2010 / Revised: 30 July 2010 / Accepted: 20 August 2010 / Published: 24 August 2010
Cited by 15 | PDF Full-text (415 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Neurotoxic Alkaloids: Saxitoxin and Its Analogs
Mar. Drugs 2010, 8(7), 2185-2211; doi:10.3390/md8072185
Received: 9 July 2010 / Revised: 12 July 2010 / Accepted: 16 July 2010 / Published: 20 July 2010
Cited by 190 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Alkaloids in Marine Algae
Mar. Drugs 2010, 8(2), 269-284; doi:10.3390/md8020269
Received: 10 December 2009 / Revised: 20 January 2010 / Accepted: 25 January 2010 / Published: 4 February 2010
Cited by 58 | PDF Full-text (349 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Terpenyl-Purines from the Sea
Mar. Drugs 2009, 7(4), 833-849; doi:10.3390/md7040833
Received: 12 November 2009 / Revised: 26 November 2009 / Accepted: 22 December 2009 / Published: 23 December 2009
Cited by 20 | PDF Full-text (175 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition
Mar. Drugs 2009, 7(4), 754-786; doi:10.3390/md7040754
Received: 30 October 2009 / Revised: 18 November 2009 / Accepted: 27 November 2009 / Published: 1 December 2009
Cited by 21 | PDF Full-text (955 KB) | HTML Full-text | XML Full-text
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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