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Marine Drugs 2009, 7(4), 833-849; doi:10.3390/md7040833
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 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.
Natural products have been a rich source of agents valued in medicine and are the most productive source of developmental drugs [1–12]. It is widely accepted that more than 80% of drug substances are natural products or have been inspired by a natural compound. Over 100 new products are under clinical development, in particular as anticancer and anti-infective agents [13–15].
Many research groups are dedicated to the isolation and identification of new natural products and other research groups use natural compounds as a models or starting materials for the preparation of derivatives that display some type of beneficial activity for human beings, mainly in the health field [16–20].
The sea is an important source of new natural compounds [21–23]. Some of them have biological, pharmacological or cytotoxic activities [24–27]. Recent research focused on marine natural products has uncovered a useful way to obtain a potentially rich source of drug candidates [28–33], where alkaloids have been found to be more effective in several therapeutic fields. The drug leads based on marine natural products have, however, created unique challenges in scaleable production and structural optimization to evaluate toxicity and enhance biological activity.
Agelasines, asmarines and related compounds are characteristic marine metabolites frequently isolated from sponge genera. Such compounds have attracted the attention of researchers because of their potent biological activities, which have been reported to include antimicrobial [34,35], antiproliferative , antileukemic , cytotoxic [34,38], antiprotozoal [39,40] and antituberculosis properties  and inhibitory effects on the enzymatic reactions of Na+,K+-ATPase . Another reason that led to the evaluation of genera of sponges is that a significant number of sponge metabolites show promising activities in antifouling assays .
This review presents a comprehensive review of the literature published about several aspects of alkylpurine metabolites from marine sponges, including the structure, isolation, biological activity and chemistry of marine metabolites with a terpene-purine structure, as well as their ability to act as antifouling agents. Emphasis is placed on their biological activity and chemistry.
2. Alkylpurine Structures
The terpene class of natural products shows wide-ranging biological activity and structural diversity. Some purine derivatives are also pharmacologically active [44–46]. Terpenylpurines are hybrid substances in which a terpene moiety (usually a diterpene moiety) is generally found as a substituent of position 7 of a 9-methyladeninium ion.
The agelasines (Figure 1) are mono- or bi- cyclic diterpenoids having a 9-methyladeninium chromophore; they are quaternary adenine salts . Ageline B and agelasine G have the general agelasine structure with a pyrrole hererocycle at diterpene moiety .
Agelasidines are not purine alkaloids. They are diterpene derivatives of hypotaurocyamine and have a guanidine unit. They may thus be considered as intermediate metabolites to agelasine F purine analogs  (Figure 3).
Asmarines are alkaloids with a unique tetrahydro[1,4]diazepino[1,2,3-g,h]purine (THDAP) structure. Asmarines are closest in structure to Agelas 9-methyladeninium-7-diterpenoids. However, they have a new heterocycle that includes a secondary hydroxylamine and they are not quaternary salts [38,51] (Figure 4).
Other alkylpurines are the methyl-, dimethyl- or trimethylpurine derivatives isolated from different marine organisms [52–55]. Doridosine, for example, an adenosine analog, is a N-methylpurine riboside  (Figure 5).
3. Sources of Agelasines, Asmarines and Related Compounds
Agelasines have been isolated from Pacific Agelas sea sponges species and asmarines have been isolated from Raspailia marine sponge species. The genus Agelas (Porifera, Agelasidae) is an interesting and enigmatic genus of sponges from both the systematic and biogeographical points of view. There are 12 well-established species that are commonly found in tropical and subtropical shallow water environments, although their distribution is not homogeneous, as there are more Agelas species in the West Indies than in the whole of the Indopacific region combined. The genus Raspailia (Demospongiae, Poecilosclerida, Microcionina, Raspailiidae) is mainly distributed in the Red Sea and Indian Ocean. Raspailia sp. from the Indian Ocean are quite different from Red Sea species and appears zoologically closer to the Kenyan Aulospangus involutos.
The quaternary 9-methyladenine derivatives of the bicyclic diterpenes agelasine A-D and ageline B, and the monocyclic diterpenes agelasine E and F have been isolated from the Okinawan sea sponge Agelas nakamurai and from the Pacific sea sponge Agelas sp. [57–62]. Agelasine F was isolated from Agelas sp. collected in Baler, Aurora, Philippines . Agelasine G was isolated from Agelas sp. collected off Konbu, Okinawa . Epi-agelasine C was isolated from Agelas mauritiana . Ageline B, agelasine F and agelasidine A were isolated from Agelas sp collected at Palau, Western Caroline Island . Agelasine H and I were isolated from Agelas mauritiana collected at Yap Island in the Federated States of Micronesia . Agelasine J, K and L  and agelasimine A and B [48,49] were isolated from the Solomon Islands orange marine sponge Agelas mauritiana. An agelasine 1 with an unusual thelepogane skeleton in the terpene moiety was isolated from the sponge Agelas nakamurai Hoshino collected in the Fly Islands, Papua, New Guinea . Another new agelasine derivative has recently been isolated from the Caribbean sponge Agelas clathrodes, this compound has been called agelasidine J, even though it is described as a new 9-methyladeninium derivative. Agelasidine A was also isolated from Agelas clathrodes .
Asmarines A-F were isolated from the marine sponge Raspailia sp. collected near Nakora Island, Dahlak Archipielago, Eritrea. [38,51,68]. Asmarines A, F, G and H were isolated from the Kenyan sponge Raspailia sp. . Asmarines A, F, I, J and K were isolated from the Nosy Be Islands (Madagascar) sponge Raspailia sp. . The wide range of biological activity makes these compounds attractive targets for synthesis. The general synthetic route to agelasines is represented in Scheme 1 (synthesis of agelasines 4 from 2) .
Agelasines A-F have been synthesized. (−)-Agelasine A is also prepared using the enantiomerically homogeneous bicyclic iodide as a key intermediate for the total synthesis of the cis-clerodane diterpenoids . Trans-clerodane (−)-agelasine B was prepared from an enantiomerically pure decalone. The key steps in the syntheses involve the stereoselective alkylation of the nitrile, the efficient coupling of the appropriate iodides to produce the clerodane skeleton, and electrochemical reduction to provide agelasine B . Another route is adenine alkylation with the alkylbromide, obtained from methyl kolavenate by sequential reduction and bromination, to give, after reductive demethoxylation and ion-exchange chromatography, agelasine B [74,75]. Agelasine C has been prepared from ent-halimic acid .
The starting material for the terpenoid side chain on agelasine D is the readily available (+)-manool, and, at least formally, also the less expensive (−)-sclareol (Scheme 2) . The synthesis was improved by Vik et al. . Agelasine E was synthesized for the first time, together with analogs with various terpenoid side chains, by treatment of N6-methoxy-9-methyl-9H-purin-6-amine with allylic bromides, to give the desired 7,9-dialkylpurinium salts together with minor amounts of the N6-alkylated isomer. The N6-methoxy group was finally removed reductively [41,79].
Until 2009, only racemic agelasine F had been synthesized. That year Gundersen et al. reported  the first synthesis of ent-agelasine F, starting from (R)-pulegone. The synthesis is considerably more efficient than a previously reported route to rac-agelasine F (Scheme 3).
Simplified analogs of agelasines and agelasimines with a β-cyclocitral derived substituent have been prepared by Proszenyak et al. . An illustrative summary of the synthesis strategies used to prepare agelasines can be found in reference . The total synthesis of agelasimine A and B has been reported from (+)-trans-dihydrocarvone [48,49].
The heterotricyclic system of asmarines was prepared from suitably substituted purines (Scheme 4). Efficient construction of the clerodane decalin core of asmarines A and B has been achieved by an asymmetric Morita-Baylis-Hillman reaction/Lewis acid-promoted annulation strategy . The tetrahydrodiazepinopurine ring skeleton 5 was prepared employing the ring-closing metathesis reaction on Boc-protected 6-allylamino-7-(propen-1-yl)purine 6 as the key step for the construction of the seven-membered ring. 7-(Propen-1-yl)purines were formed by a novel rearrangement of 7-allylpurines under basic conditions. Boc-protected N6,7-diallylpurine also participated in ring-closing metathesis reaction to give the eight-membered ring analog of the diazepinopurine . Alternatively, tetrahydrodiazepinopurine ring skeleton 5 can be constructed by formation of bond “a” from compound 7  and by formation of bond “b” from compound 8 [36,85]. Another methodology for the preparation of asmarine analogs was developed by Pappo et al. Three cyclization methods were applied to prepare the 9,9-disubstituted 10-hydroxy-tetrahydrodiazepino system: namely, aminomercurization, iodocyclization, and acid-catalyzed cyclization. The O-(3,4-dimethoxybenzyl group of the NOH functionality and cyanoethyl group of the N-9 atom were found to be the most suitable protecting groups .
In order to access a key component to complete the synthesis of asmarine B, Rodgen et al.  developed a methodology involving the allylboration of imines followed by subsequent oxidation to form the desired hydroxylamine. Nevertheless, the total synthesis of asmarine B has still not been published, although other synthetic strategies towards key asmarine intermediates have [88,89].
4. Biological Activity of Marine Terpenyl-Purine Alkaloids
4.1. Antifouling activity
There is an increasing interest in exploring the antifouling potential of natural products because there is a clear need to develop new non-toxic or environmentally benign antifouling alternatives that will be efficient against the most severe fouling organisms such as barnacles, blue mussels, bryozoans and algae. Many sponges have been shown to synthesize toxic metabolites to prevent predation, and hence other organisms frequently attach sponges to themselves for their protection .
Agelasine D, together with two of its analogs, displays a strong inhibitory effect on the settlement of Balanus improvisus cypris larvae (EC50 0.11–0.30 μM). None of these three compounds affected larval mortality. When after 24 h exposure to the compounds the cyprids were transferred to fresh seawater, the settlement frequency was completely recovered in comparison with the controls. These properties make agelasine D and analogs highly attractive candidates as antifouling agents in future marine coatings . The antifouling activity of epi-agelasine C against Ulva spores is not as high as that of CuSO4 (positive control); however, epi-agelasine C shows lethal activity against Ulva fronds at 50 ppm. Antimicroalgal activity against Oscillatoria amphibian (Cyanophyceae), Skeletonema costatum (Diatomophyceae), Brachiomonas submaria (Chlorophyceae) and Prorocentrum micans (Dinophyceae) has been observed at 1.0–2.5 ppm, so this compound seems to be useful as a measure to counter red tide .
4.2. Antituberculosis activity
Tuberculosis is still a major health problem worldwide. Although the treatment regimens currently available can cure almost all tuberculosis drug-susceptible cases, problems such as the length of treatment, the need for multidrug therapy, the emergence of drug resistance, HIV co-infection, and persistent Mycobacterium tuberculosis bacilli, highlight the need for new anti-tuberculosis drugs. New anti-tubercular drug regimens are clearly needed to reduce the time required for a lasting cure and to treat the expanding problem of drug- and multidrug-resistant (MDR) Mycobacterium tuberculosis strains [91,92]. The strategies to search for new antituberculosis drugs involve screening libraries of small molecules and natural products or the previous identification of targets crucial to the microorganism, followed by the subsequent design of new molecules. Antituberculosis compounds from natural sources have enormous potential for the development of new drugs that have shown not only antimicrobial activity per se but also inhibition of the mechanism of resistance (e.g., efflux pumps) or modulation of the immune response (e.g., macrophage stimulation) [93,94].
In vitro, agelasine F inhibits some drug-resistant strains of Mycobacterium tuberculosis and inhibits the growth of tuberculosis H37Rv at concentrations as low as 3.13 μg/mL. The metabolite is also equally potent against a range of single drug-resistant strains including, isoniazid, rifampicin, ethambutol and ethionamid. Activity against M. tuberculosis residing within macrophages requires concentrations of 13–22 μg/mL, which are below the IC50 for Vero cells (34 μg/mL) [63,82]. The weak bactericidal activity of agelasine F, indicated by a higher value for EC99, together with the moderate toxicity to Vero cells, disqualifies agelasine F as a drug per se. However, it might serve as an interesting lead for the design and synthesis of a more active molecule .
Only modest antimycobacterial activity has been found for agelasine E  and agelasine analogs with free NH2 in the position 6 of the purine, but several agelasine analogs still carrying the MeO-directing group at N-6 are highly potent inhibitors against M. tuberculosis. A relatively long N-7 side chain is required for significant activity. M. tuberculosis has an extremely thick and waxy cell wall, which is an effective barrier for many chemicals. Accordingly, effective drugs should have a reasonable degree of lipophilicity in order to penetrate that wall. This may explain why more polar compounds are generally less efficient than less polar ones. However, in some N-6-alkylated agelasine isomers, formed as by-products in the alkylating step, significant activities have been found when the terpenoids side chain is relatively large. Furthermore, while the N-6-methoxy-9-methyladenine is essentially inactive, the simple 9-methyladenine exhibits an MIC against M. tuberculosis at 6.25 μg/mL of 94% (positive control, rifampicin) . Reasonable antimycobacterial activity has also been reported for some simple 9-benzyladenines . 7-Alkyl, 7-benzyl and 7-geranyl purinamine derivatives are more or less inactive against the bacteria examined. In contrast, (2E,6E)-farnesyl and isomeric (2E,6Z)-farnesyl derivatives exhibit a strong inhibitory activity against Mycobacterium tuberculosis .
4.3. Antimicrobial activity
Infectious diseases caused by bacteria, fungi, viruses and parasites are still a major threat to public health despite the tremendous progress in human medicine. Natural products, either as pure compounds or as standardized extracts, provide unlimited opportunities for new anti-infective drug leads because of the unmatched availability of their chemical diversity .
Some agelasine analogs show antibacterial activities. Agelasine D and close analogs display a broad spectrum of antibacterial activities, including effects on M. tuberculosis, Gram-positive and Gram-negative bacteria (both aerobes and anaerobes). (2E,6E)-farnesyl and isomeric (2E,6Z)-farnesyl derivatives, on the other hand, exhibit a profound inhibitory activity against Staphylococcus aureus. These compounds are also active against Bacteroides fragilis and Bacteroides thetaiotaomicron (anaerobe). The geometry of the terpenoid side chain appears to have no significant influence on antibacterial activity. Geranylgeranyl purine is also active against Streptococus pyrogenes and Enterobacter facealis, but not against Pseudomonas aeruginosa, in the concentration range examined. Reduced inhibitory activity against bacteria has been found for phytyl derivatives, indicating that the unsaturation in the side chain is important for the antibacterial activity [34,35].
Several samples of Agelas sp. containing agelasine F, agelasidine A and ageline B, show antimicrobial activity against Gram-positive bacteria S. aureus and two fungi: Candida albicans and C. utilis . Pure samples of ageline B and angelasine F inhibit the growth of S. aureus, B. subtilis and C. albicans. Agelasine F and agelasidine A are lethal to goldfish, Carassius auratus (ichthyotoxicity) .
Ent-agelasine F exhibits antimicrobial activity: MIC Staphylococcus aureus 2 μg/mL, and MIC Escherichia coli 16 μg/mL . Epi-agelasine C does not exhibit antibacterial activity against Staphylococcus aureus, Vibrio costicola, Escherichia coli or Bacillus subtilis .
Agelasine A and H are inactive against P. aeuroginosa, S. aureus, Aspergillus niger and Saccharomuces cerevisiae at concentrations of 200, 100, 10 and 1 μg/mL. Agelasine B and ageline B inhibit S. cerevisiae at 10 μg/mL. Agelasine F inhibits A. niger at 100 μg/mL and S. cerevisiae at 10 μg/mL. Agelasine I 7 inhibits S. cerevisiae at 200 μg/mL. Agelasimine analogs are strong inhibitors of S. aureus and E. coli .
4.4. Antiprotozoal activity
Agelasine D, other agelasine analogs and related structures have been screened for their inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and Tripanosoma cruzi, as well as for toxicity against MCR-5 fibroblast cells, in order to assess the selectivity of their action . A higher activity was found for agelasine D (IC50 0.63 μM) against P. falciparum than agelasine J (IC50 6.6 μM), agelasine K (IC50 8.3 μM) and L (IC50 18 μM). The selectivity index of agelasine D for antimalarial action [SI: IC50 (MCR-5 fibroblast)/IC50 (Plasmodium falciparum)] was 23 and it also displays a significant inhibitory action against the other parasites examined. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), in that study two agelasine analogs were identified as hits for leishmaniasis and for Chagas’ disease . Agelasine J, K and L display in vitro antimalarial activity against Plasmodium falciparum .
4.5. Cytotoxic activity
Some agelasine and agelasimine analogs exert a strong cytotoxic activity against several cancer cell lines (MIC 0.1 μM for the most potent compound), including a drug-resistant renal cell line .
Agelasine G shows cytotoxic activity against lymphoma L1210 cells in vitro, with an IC50 value of 3.1 μg/mL . The agelasine analog (2′E,6E,10′E)-6-methoxyamino-9-methyl-7-(3,7,11,15-tetra-methyl-2,6,10,14-hexadecatetraenyl)-7H-purinium, exhibits a powerful activity against cancer cell lines. This agelasine analog is also a potent inhibitor of ACHN (renal adenocarcinoma cells) growth and is more effective against the primary multidrug-resistant (MDR) cell line ACHN than any of the anticancer drugs used as positive control (doxorubicin, cisplatin and paclitaxel) .
Asmarines A and B have cytotoxic activity against cell cultures of P-388 murine leukemia, HT-29 human colon carcinoma, and MEL-28 human melanoma cells. Asmarine B (IC50 0.12–0.24 μM) is more active than asmarine A (IC50 1.18 μM) and shows higher activity against human lung and human colon carcinoma .
Asmarines A and B and some synthetic analogs have been tested for cytotoxic activity against DU-145 prostate, IGROV-ET ovarian, A-549 NSCL, PANC1 pancreas and LOVO colon cancer cell lines. Synthetic compounds were all found to be at least one order of magnitude less active than asmarine B (GI50 0.04–0.5 μg/mL). The cyclization modes for 9-mono and 9,9-disubstituted tetra-hydro[1,4]diazepino[1,2,3-g,h]purine structure can form the basis of SAR studies of asmarine analogs, and provide a route for the total synthesis of asmarine A starting from the appropriate diterpene and purine . The biological target of asmarine A and B is not known .
4.6. Inhibitory effect on the enzymatic reaction of Na+, K+-ATPase
It is well established that Na+,K+-ATPase hydrolyzes ATP to provide the energy for the active transport of Na+ and K+ across the cell membrane. This enzyme acts as the electrogenic Na+, K+ pump and contributes to the membrane excitability of several cells. Inhibition of Na+,K+-ATPase has physiologically important roles, such as the cardiotonic effect .
The Na+,K+-ATPase from brain or kidney and sarcoplasmic reticulum Ca2+-ATPase were potently inhibited by agelasidine C and agelasine B and exert a less potent inhibition on heart Na+,K+-ATPase. The ionized moiety of agelasidine C and the long nonpolar side chains in agelasine B play important roles in their inhibitory action. The inhibition of Na+,K+-ATPase by agelasidine C or agelasine B is almost reversed by diluting with inhibitor-free solution . Agelasin B and some analogs show inhibitory activity against Na+,K+-ATPase reactions at 10−4 M .
Other activities of terpenylpurines, such as the inhibition of adenosine transfer into rabbit erythrocytes, their Ca2+-channel antagonistic action and an α1 adrenergic blockade, have been reported .
Moreover, the biological properties of some methylpurines are also very interesting. In vivo doridosine causes hypotension, a reduction in heart rate, muscle relaxation and anti-inflammatory effects through adenosine A1 and A2 receptors [56,100]. The affinity prediction on A1 adenosine receptor agonists has been determined by the chemometric approach . 1-Methylherbipoline is a serine protease inhibitor .
Some natural products have a profound impact on human health. The biosynthetic engine of Nature produces innumerable secondary metabolites with distinct biological properties that make them valuable as health products or as structural templates for drug discovery.
Marine sponges of the genera Agela and Raspailia have been demonstrated to be a rich source of bioactive alkaloids. Many terpenylpurine alkaloids isolated from those genera are of considerable interest with regard to their biological activities. Furthermore, some of them have exhibited promising activities in future marine coatings as antifouling alternatives against the most severe fouling organisms, one of the most serious problems of marine technology.
Agelasines, asmarines and related structures display cytotoxicity and antiprotozoal, antimicrobial, antituberculosis activity, among others. Identification of the hits as well as other SAR studies will be valuable for the design of more potent and selective potential drugs against several diseases.
The author would like to express her gratitude to the Regional Government of Castile & Leon (Consejería de Educación, SA-18/09).
- Newman, J; Cragg, G. Natural products in medicinal chemistry. Bioorg Med Chem 2009, 17, 2120. [Google Scholar]
- Li, M-Y; Xiao, O; Pan, JY; Wu, J. Natural products from semi-mangrove flora: Source, chemistry and bioactivities. Nat Prod Rep 2009, 26, 281–298. [Google Scholar]
- Newman, DJ; Cragg, GM; Kingston, DGI. Natural products as pharmaceuticals and sources for lead structures. In The Practice of Medicinal Chemistry, 3rd ed; Wermuth, CG, Ed.; Academic Press: London, UK, 2003; pp. 159–186. [Google Scholar]
- Newman, DJ; Cragg, GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007, 70, 461–477. [Google Scholar]
- Newman, DJ; Cragg, GM; Snader, KM. Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod 2003, 66, 1022–1037. [Google Scholar]
- Ganesan, A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol 2008, 12, 306–317. [Google Scholar]
- Newman, DJ. Natural products as leads to potential drugs: An old process or the new hope for drug discovery. J Med Chem 2008, 51, 2589–2599. [Google Scholar]
- Galm, U; Shen, B. Natural products drug discovery: The times have never been better. Chem Biol 2007, 14, 1098–1104. [Google Scholar]
- Paterson, I; Anderson, EA. The renaissance of natural products as drug candidates. Science 2005, 310, 451–453. [Google Scholar]
- Harvey, AL. Natural products as a screening resource. Curr Opin Chem Biol 2007, 11, 480–484. [Google Scholar]
- Rishton, GM. Natural products as a robust source of new drugs and drug leads: Past successes and present day issues. Am J Cardiol 2008, 101(Suppl), 43D–49D. [Google Scholar]
- Lam, KS. New aspects of natural products in drug discovery. Trends Microbiol 2007, 15, 279–289. [Google Scholar]
- Harvey, AL. Natural product in drug discovery. Drug Discov Today 2008, 13, 894–901. [Google Scholar]
- Butler, MS. Natural product to drug: Natural products derived compounds in clinical trials. Nat Prod Rep 2008, 25, 475–516. [Google Scholar]
- Butler, MS. Natural products to drugs: Natural products derived compounds in clinical trials. Nat Prod Rep 2005, 22, 162–195. [Google Scholar]
- Wilson, RM; Danishefsky, SJ. Small molecule natural products in the discovery of therapeutic agents: The synthesis connection. J Org Chem 2006, 71, 8329–8351. [Google Scholar]
- Shaw, JT. Naturally diverse: Highlights in versatile synthetic methods enabling target and diversity oriented synthesis. Nat Prod Rep 2009, 26, 11–26. [Google Scholar]
- Langer, T; Laggner, C; Rollinger, JM; Stuppner, H. Pharmacophore-based screening for the successful identification of bio-active natural products. Chimia 2007, 61, 350–354. [Google Scholar]
- Gordaliza, M. Natural products as leads to anticancer drugs. Clin Transl Oncol 2007, 9, 767–776. [Google Scholar]
- Pla, D; Marchal, A; Olsen, CA; Albericio, F; Álvarez, M. Modular total synthesis of lamellarin D. J Org Chem 2005, 70, 8231–8234. [Google Scholar]
- Blunt, JW; Copp, BR; Hu, WP; Munro, MHG; Northcote, PT; Prinsep, MR. Marine natural products. Nat Prod Rep 2009, 26, 170–244. [Google Scholar]
- Morris, JC; Phillips, AJ. Marine natural products: Synthetic aspects. Nat Prod Rep 2009, 26, 245–265. [Google Scholar]
- Skropeta, D. Deep-sea natural products. Nat Prod Rep 2008, 25, 1131–1166. [Google Scholar]
- Haefner, B. Drugs from the deep: Marine natural products as drug candidates. Drug Discov Today 2003, 8, 536–544. [Google Scholar]
- Mayer, AMS; Gustafson, KR. Marine pharmacology in 2005–2006: Antitumour and cytotoxic compounds. Eur J Cancer 2008, 44, 2357–2387. [Google Scholar]
- Mayer, AMS; Rodríguez, AD; Berlinck, RGS; Hamann, MT. Marine pharmacology in 2005–6: Marine compounds with anthelmintic, antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action. Biochim Biophys–Gen 2009, 1790, 283–308. [Google Scholar]
- Cuevas, C; Francesch, A. Development of Yondelis® (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat Prod Rep 2009, 26, 322–333. [Google Scholar]
- Glaser, KB; Mayer, AMS. A renaissance in marine pharmacology: From preclinical curiosity to clinical reality. Biochem Pharmacol 2009, 78, 440–448. [Google Scholar]
- Molinski, TF; Dalisay, DS; Lievens, SL; Saludes, JP. Drug development from marine natural products. Nat Rev Drug Discov 2009, 8, 69–85. [Google Scholar]
- Bugni, TS; Richads, B; Bhoite, L; Cimbora, D; Harper, MK; Ireland, CM. Marine natural product libraries for high-throughput screening and rapid drug discovery. J Nat Prod 2008, 71, 1095–1598. [Google Scholar]
- Gordaliza, M; Miguel del Corral, JM; Mahiques, MM; San Feliciano, A; García-Grávalos, MD. Terpenequinone with antitumor activity. PCT Int Appl EP 0731078 A1 1994. [Google Scholar]
- Esteban, G; Rincón, R; Csákÿ, AG; Plumet, J. A convenient synthesis of the central core of helioporins, seco-pseudopterosins and pseudopterosins via BCA-annulation sequence. Nat Prod Comm 2008, 3, 495–504. [Google Scholar]
- Pla, D; Albericio, F; Alvarez, M. Recent advances in lamellarin alkaloids: Isolation, synthesis and activity. Anti-Cancer Agents Med Chem 2008, 8, 746–760. [Google Scholar]
- Vik, A; Hedner, E; Charnock, C; Tangen, LW; Samuelsen, O; Larsson, R; Bohlin, L; Gundersen, L-L. Antimicrobial and cytotoxic activity of agelasine and agelasimine analogs. Bioorg Med Chem 2007, 15, 4016–4037. [Google Scholar]
- Capon, RJ; Faulkner, DJ. Antimicrobial metabolites from a Pacific sponge. Agelas sp J Am Chem Soc 1984, 106, 1819–1822. [Google Scholar]
- Pappo, D; Shimony, S; Kashman, Y. Synthesis of 9-substituted tetrahydrodiazepinopurines: Studies toward the total synthesis of asmarines. J Org Chem 2005, 70, 199–206. [Google Scholar]
- Ishida, K; Ishibashi, M; Shigemori, H; Sasaki, T; Kobayashi, J. Agelasine G, a new antileukemic alkaloid from the Okinawan marine sponge Agelas sp. Chem Pharm Bull 1992, 40, 766–767. [Google Scholar]
- Yosief, T; Rudi, A; Kashman, Y. Asmarines A-F, novel cytotoxic compounds from the marine sponge Raspailia species. J Nat Prod 2000, 63, 299–304. [Google Scholar]
- Gademann, K; Kobylinska, J. Antimalarial natural products of marine and freshwater origin. Chem Rec 2009, 9, 187–198. [Google Scholar]
- Vik, A; Proszenyak, A; Vermeersch, M; Cos, P; Maes, L; Gundersen, L-L. Screening of agelasine D and analogs for inhibitory activity against pathogenic protozoa; identification of hits for visceral leishmaniasis and chagas disease. Molecules 2009, 14, 279–288. [Google Scholar]
- Bakkestuen, AK; Gundersen, L-L; Petersen, D; Utenova, BT; Vik, A. Synthesis and antimycobacterial activity of agelasine E and analogs. Org Biomol Chem 2005, 3, 1025–1033. [Google Scholar]
- Kobayashi, M; Nakamura, H; Wu, H; Kobayashi, J; Ohizumi, Y. Mode of inhibition of brain sodium-potassium ATPase by agelasidines and agelasines from a sea sponge. Arch Biochem Biophys 1987, 259, 179–184. [Google Scholar]
- Sjogren, M; Dahlstrom, M; Hedner, E; Jonsson, PR; Vik, A; Gundersen, LL; Bohlin, L. Antifouling activity of the sponge metabolite agelasine D and synthesised analogs on Balanus improvisus. Biofouling 2008, 244, 251–258. [Google Scholar]
- Atta-ur-Rahman; Choudhary, MI. The Alkaloids; Brossi, A, Ed.; Academic Press: New York, NY, USA, 1990; Volume 38, pp. 225–323. [Google Scholar]
- Aniszewski, T. Alkaloids. In Secrets of Life; Elsevier: Amsterdam, The Netherland, 2007; pp. 237–286. [Google Scholar]
- Christophersen, C. Marine Alkaloids. In The Alkaloids: Chemistry and Pharmacology; Brossi, A, Ed.; Academic Press Inc: Orlando, FL, USA, 1985; Volume 24, pp. 25–111. [Google Scholar]
- Appenzeller, J; Mihci, G; Martin, M-T; Gallard, J-F; Menou, J-L; Boury-Esnault, N; Hooper, J; Petek, S; Chevalley, S; Valentin, A. Agelasines J, K, and L from the Solomon Islands marine sponge Agelas cf mauritiana. J Nat Prod 2008, 71, 1451–1454. [Google Scholar]
- Ohba, M; Kawase, N; Fujii, T. Total synthesis of (±)-agelasimine A, (±)-agelasimine B an (±)-purino-diterpene and the structure of diacetylagelasimin A. J Am Chem Soc 1996, 118, 8250–8257. [Google Scholar]
- Ohba, M; Iizuca, K; Ishibashi, H; Fujii, T. Synthesis and absolute configurations of marine sponge purines (+)-agelasimine A and (+)-agelasimine B. Tetrahedron 1997, 53, 16977–16986. [Google Scholar]
- Medeiros, MA; Lourenco, A; Tavares, MR; Curto, MJ; Marcelo, F; Savluchinske, S; Roseiro, JC. (−)-Agelasidine A from Agelas clathrodes. Z Naturforsch C J Biosci 2006, 61, 472–476. [Google Scholar]
- Yosief, T; Rudi, A; Stein, Z; Goldberg, I; Garcia Gravalos, MD; Schleyer, M; Kashman, Y. Asmarines A-C; three novel cytotoxic metabolites from the marine sponge Raspailia sp. Tetrahedron Lett 1998, 39, 3323–3326. [Google Scholar]
- Kimura, J; Ishizuka, E; Nakao, Y; Yoshida, WY; Scheuer, PJ; Kelly-Borges, M. Isolation of 1-methylherbipoline salts of halisulfate-1 and of suvanine as serine protease inhibitors from a marine sponge Coscinoderma mathewsi. J Nat Prod 1998, 61, 248–250. [Google Scholar]
- Mitchell, SS; Whitehill, AB; Trapido-Rosenthal, HG; Ireland, CM. Isolation and characterization of 1,3-dimethylisoguanine from the Bermudian sponge Amphimedon viridis. J Nat Prod 1997, 60, 727–728. [Google Scholar]
- Tasdemir, D; Mangalindan, GC; Concepcion, GP; Harper, MK; Ireland, CM. 3,7-Dimethylguanine, a new purine from a Philippine sponge Zyzzya fuliginosa. Chem Pharm Bull 2001, 49, 1628–1630. [Google Scholar]
- Cafieri, F; Fattorusso, Er; Mangoni, A; Taglialetela-Scafati, O. 3,7-Dimethylisoguanine, two novel alkaloids from the marine sponge Agelas longissima. Tetrahedron Lett 1995, 36, 7893–7896. [Google Scholar]
- Fuhrman, FA; Fuhrman, GF; Kim, YH; Pavelki, LA; Mosher, HS. Doridosine: A new hipotensive N-methylpurine riboside from the nudibranch Anisodoris nobilis. Science 1980, 207, 193–195. [Google Scholar]
- Cullen, E; Devlin, JP. Agelasine, a novel quaternary 9-methyladenine from the sponge Agelas dispar. Can J Chem 1975, 53, 1690–1691. [Google Scholar]
- Fathi-Afshar, R; Allen, TM. Biological active metabolites from Agelas mauritania. Can J Chem 1988, 66, 45–50. [Google Scholar]
- Nakamura, H; Wu, H; Ohizumi, Y; Hirata, Y. Physiologically active marine natural products from Porifera. IV. Agelasine A, B, C and D, novel bicyclic diterpenoids with a 9-methyladeninium unit possessing inhibitory effects on sodium-potassium ATPase from the Okinawan sea sponge Agelas sp. Tetrahedron Lett 1984, 25, 2989–2989. [Google Scholar]
- Wu, H; Nakamura, Hi; Kobayashi, J; Kobayashi, M; Ohizumi, Y; Hirata, Y. Physiologically active marine natural products from Porifera. XII. Structures of agelasines, diterpenes having a 9-methyladeninium chromophore isolated from the Okinawan marine sponge Agelas nakamurai Hoshino. Bull Chem Soc Jpn 1986, 59, 2495–2504. [Google Scholar]
- Fathi-Afshar, R; Allen, TM. Some pharmacological activities of novel adenine-related compounds isolated from a marine sponge Agelas mauritiana. Can J Physiol Pharmacol 1989, 67, 276–281. [Google Scholar]
- Wu, H; Nakamura, H; Kobayashi, J; Ohizumi, Y. Agelasine E and F, novel monocyclic diterpenoids with a 9-methyladeninium unit possessing inhibitory effects on Na,K-ATPase isolated from the Okinawian sea sponge Agelas nakamurai Hoshino. Tetrahedron Lett 1984, 25, 3719–3722. [Google Scholar]
- Mangalindan, GC; Talaue, MT; Cruz, LJ; Franzblau, SG; Adams, LB; Richardson, AD; Ireland, CM; Concepcion, GP. Agelasine F from a Philippine Agelas sp. sponge exhibits in vitro antituberculosis activity. Planta Med 2000, 66, 364–365. [Google Scholar]
- Hattori, T; Adachi, K; Shizuri, Y. New agelasine compound from the marine sponge Agelas mauritiana as an antifouling substance against macroalgae. J Nat Prod 1997, 60, 411–413. [Google Scholar]
- Fu, X; Schmitz, FJ; Tanner, RS; Kelly-Borges, M. Agelasines H and I, 9-methyladenine-containing diterpenoids from an Agelas sponge. J Nat Prod 1998, 61, 548–550. [Google Scholar]
- Iwagawa, T; Kaneko, M; Okamura, H; Nakatani, M; Van, S; Rob, WM. New alkaloids from Paua New Guinea sponge Agelas nakamurai. J Nat Prod 1998, 61, 1310–1312. [Google Scholar]
- Pina, IC; Crews, P; Tenney, K. A new agelasine derivative from the Caribbean sponge Agelas clathrodes. Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA, USA, September 10–14, 2006.
- Kashman, Y; Rudi, A; Yosief, T; Gravalos, DG. Cytotoxic alkaloid derivatives including asmarine A and B isolated from a sponge. PCT Int Appl WO 9933832 A1 1999. [Google Scholar]
- Rudi, A; Shalom, H; Schleyer, M; Benayahu, Y; Kashman, Y. Asmarines G and H and barekol, three new compounds from the marine sponge Raspailia sp. J Nat Prod 2004, 67, 106–109. [Google Scholar]
- Rudi, A; Aknin, M; Gaydou, E; Kashman, Y. Asmarines I, J, and K and nosyberkol: Four new compounds from the marine sponge Raspailia sp. J Nat Prod 2004, 67, 1932–1935. [Google Scholar]
- Roggen, H; Gundersen, L-L. Synthetic studies directed towards agelasine analogs-synthesis, tautomerism, and alkylation of 2-substituted N-methoxy-9-methyl-9H-purin-6-amines. Eur J Org Chem 2008, 30, 5099–5106. [Google Scholar]
- Piers, E; Breau, ML; Han, Y; Plourde, Guy, L; Yeh, W-L. Total synthesis of cis-clerodane diterpenoids: (−)-Agelasine A and (+)-(3R,4S,5R,8S,9R,10S)-3,4-epoxyclerod-13-en-15,16-olide. J Chem Soc, Perkin Trans 1: Org Bioorg Chem 1995, 8, 963–966. [Google Scholar]
- Piers, E; Roberge, JY. Total syntheses of the diterpenoids (−)-kolavenol and (−)-agelasine B. Tetrahedron Lett 1992, 33, 6923–6926. [Google Scholar]
- Iio, H; Asao, K; Tokoroyama, T. Syntheses of agelasin B and its analogs. J Chem Soc, Chem Com 1985, 774–775. [Google Scholar]
- Asao, K; Monden, M; Asada, To; Iio, H; Tokoroyama, T. Synthetic studies on clerodane diterpenoids. Asymmetric synthesis of (−)-kolavenic acid and synthesis of agelasins. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1985, 27, 137–143. [Google Scholar]
- Marcos, IS; Garcia, N; Sexmero, MJ; Basabe, P; Diez, D; Urones, JG. Synthesis of (+)-agelasine C. A structural revision. Tetrahedron 2005, 61, 11672–11678. [Google Scholar]
- Utenova, BT; Gundersen, L-L. Synthesis of (+)-agelasine D from (+)-manool. Tetrahedron Lett 2004, 45, 4233–4235. [Google Scholar]
- Vik, A; Hedner, E; Colin, C; Samuelsen, O; Larsson, R; Gundersen, L-L; Bohlin, L. (+)-Agelasine D: Improved synthesis and evaluation of antibacterial and cytotoxic activities. J Nat Prod 2006, 69, 381–386. [Google Scholar]
- Bakkestuen, AK; Gundersen, LL. Synthesis of (+)-trixagol and its enantiomer, the terpenoid side chain of (−)-agelasine E. Tetrahedron 2003, 59, 115–121. [Google Scholar]
- Proszenyak, A; Braendvang, M; Charnock, C; Gundersen, L-L. The first synthesis of ent-agelasine F. Tetrahedron 2009, 65, 194–199. [Google Scholar]
- Proszenyak, A; Charnock, C; Hedner, E; Larsson, R; Bohlin, L; Gundersen, L-L. Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a beta-cyclocitral derived substituent. Arch Pharm 2007, 340, 625–34. [Google Scholar]
- Mancini, I; Defant, A; Guella, G. Recent synthesis of marine natural products with antibacterial activities. Anti-Infect Agents Med Chem 2007, 6, 17–48. [Google Scholar]
- Vik, A; Gundersen, LL. Synthetic studies directed towards asmarines; construction of the tetrahydrodiazepinopurine moiety by ring closing metathesis. Tetrahedron Lett 2007, 48, 1931–1934. [Google Scholar]
- Ohba, M; Tashiro, T. Preparatory study for the synthesis of the marine sponge alkaloids asmarines A-F: Synthesis of their heterocyclic portions. Heterocycles 2002, 57, 1235–1238. [Google Scholar]
- Pappo, D; Kashman, Y. Synthesis of 9-substituted tetrahydrodiazepinopurines-asmarine A analogues. Tetrahedron 2003, 59, 6493–6501. [Google Scholar]
- Rodgen, SA; Schaus, SE. Efficient construction of the clerodane decalin core by an asymmetric Morita-Baylis-Hillman reaction/Lewis acid promoted annulation strategy. Ang Chem, Int Ed 2006, 45, 4929–4932. [Google Scholar]
- Rodgen, SA; Schaus, SE. Total synthesis of Asmarine B. Abstracts of Papers, 234th ACS National Meeting, Boston, MA, USA, August 19–23, 2007.
- Pappo, D; Rudi, A; Kashman, Y. A synthetic approach towards the synthesis of asmarine analogues. Tetrahedron Lett 2001, 42, 5941–5943. [Google Scholar]
- Zhang, F-L; Vasella, A. Synthesis of spiropyrimidodiazepines and spirodiazepinopurines by tandem nitroso-ene/Diels-Alder reactions. Helv ChimActa 2007, 90, 2315–2329. [Google Scholar]
- Clare, AS. Towards non-toxic antifouling. J Mar Biotechnol 1998, 6, 3–6. [Google Scholar]
- Nikomenko, BV; Protopopova, M; Samala, R; Einck, I; Nacy, CA. Drug therapy of experimental tuberculosis (tb): Improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs. Antimicrob Agents Chemother 2007, 51, 1563–1565. [Google Scholar]
- Copp, BR; Pearce, AN. Natural product growth inhibitors of Mycobacterium tuberculosis. Nat Prod Rep 2007, 24, 278–297. [Google Scholar]
- Kishore, N; Mishra, BB; Tripathi, V; Tiwari, VK. Alkaloids as potential antitubercular agents. Fitoterapia 2009, 80, 149–163. [Google Scholar]
- Palomino, JC; Ramos, DF; da Silva, PA. New anti-tuberculosis drugs: Strategies, sources and new molecules. Curr Med Chem 2009, 16, 1898–1904. [Google Scholar]
- Alksnis, E; Korneeva, D; Lukevics, E. Adenine and uracil derivatives with antitubercular activity. Chem Het Com 2001, 37, 743–746. [Google Scholar]
- Cos, P; Vlietinck, AJ; Berghe, DV; Maes, L. Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’. J Ethnopharmacol 2006, 106, 290–302. [Google Scholar]
- Gademann, K; Kobylinska, J. Antimalarial natural products of marine and freshwater origin. Chem Rec 2009, 9, 187–198. [Google Scholar]
- Nakamura, H; Kobayashi, J; Wu, H; Deng, S; Kobayashi, M; Nakamura, Y; Ohizumi, Y; Hirata, Y. Enzyme inhibitors isolated from Okinawan marine sponges. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1985, 27, 608–615. [Google Scholar]
- Lio, H; Asao, K; Tokoroyama, T. Syntheses of agelasin B and its analogues. J Chem Soc, Chem Commun 1985, 774–775. [Google Scholar]
- Tao, P-L; Yen, M-H; Shyu, W-S; Chern, J-W. Doridosine derivatives: Binding at adenosine receptors and in vivo effect. Eur J Pharmacol 1993, 243, 135–139. [Google Scholar]
- Fossa, P; Mosti, L; Bondavalli, F; Schenone, S; Ranise, A; Casolino, C; Forina, M. Affinity prediction on A1 adenosine receptor agonists: The chemometric approach. Bioorg Med Chem 2006, 14, 1348–1363. [Google Scholar]
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