Introduction 4489 1.1. Indole Moiety in Drugs 4489 1.2. Serotonin Receptors: Possible Targets for Neurologically Active Marine Indole Alkaloids 4489 2. Natural Indole Alkaloids of Marine Origin 4490 3. Synthetic Indole Alkaloids 4491 4. In the Pipeline: Novel Tryptamine-and Indole-Derived Structures 4495 5. Conclusions 4495 6. Acknowledgments 4496 7. References 4496

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The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities.

The oceans are a unique resource that provide a diverse array of natural products, primarily from invertebrates such as sponges, tunicates, bryozoans, and molluscs, and from marine bacteria and cyanobacteria. As infectious diseases evolve and develop resistance to existing pharmaceuticals, the marine environment provides novel leads against fungal, parasitic, bacterial, and viral diseases. Many marine natural products have successfully advanced to the late stages of clinical trials, including dolastatin 10, ecteinascidin-743, kahalalide F, and aplidine, and a growing number of candidates have been selected as promising leads for extended preclinical assessment. Although many marine-product clinical trials are for cancer chemotherapy, drug resistance, emerging infectious diseases, and the threat of bioterrorism have all contributed to the interest in assessing natural ocean products in the treatment of infectious organisms. In this review, we focus on the pharmacologically tested marine leads that have shown in-vivo efficacy or potent in-vitro activity against infectious and parasitic diseases.

Pure natural products isolated from marine sponges, algae, and cyanobacteria were examined for antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) solution-based chemical assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) cellular-based assay. The DCFH system detects only antioxidants that penetrate cellular membranes. Potent antioxidants were identified and the results from each system compared. The algal metabolites cymopol (1), avrainvilleol (3), and fragilamide (4), and the invertebrate constituent puupehenone (5) showed strong antioxidant activity in both systems. Several compounds were active in the DPPH assay but significantly less active in the DCFH system. The green algal metabolite 7-hydroxycymopol (2) was isolated from Cymopolia barbataand its structure determined. Compound 2 was significantly less active in the DCFH system than cymopol (1). The sponge metabolites (1S)-(+)-curcuphenol (6), aaptamine (7), isoaaptamine (8), and curcudiol (9) and the cyanobacterial pigment scytonemin (10) showed strong antioxidant activity in the DPPH assay, but were relatively inactive in the DCFH system. Thus, cellular uptake dramatically affects the potential significance of antioxidants discovered using only the DPPH assay. The apparent "proantioxidants" hormothamnione A diacetate (11) and Laurencia monomer diacetate (12) require metabolic activation for antioxidant activity. Significant advantages are achieved using both a solution- and cellular-based assay to discover new antioxidants.

Eleven manzamine type alkaloids, two β-carbolines, and five nucleosides have been isolated from an Indonesian sponge. Among these are the previously characterized 12,34-oxamanzamine A, 12,34-oxamanzamine E, manzamine A (1), 8-hydroxymanzamine A, 6-deoxymanzamine X, manzamine E (2), manzamine X, manzamine F (4), norharman, thymine, 2′,3′-didehydro-2′,3′-dideoxyuridine, uracil, thymidine, and 2′-deoxyuridine. The structures for the five new compounds have been assigned as 32,33-dihydro-31-hydroxymanzamine A (3), 32,33-dihydro-6-hydroxymanzamine A-35-one (5), des-N-methylxestomanzamine A (6), 32,33-dihydro-6,31-dihydroxymanzamine A (7), and 1,2,3,4-tetrahydronorharman-1-one (8), on the basis of NMR and X-ray data. The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented. The structural revision of two previously reported pyrazoles as uracil and thymine is also discussed.Manzamines are unique β-carboline alkaloids isolated from Indo-Pacific sponges and characterized by having an intricate nitrogen-containing polycyclic system. In 1986, Higa and co-workers first reported manzamine A from the Okinawan sponge of the genus Haliclona. 1 These compounds exhibit a diverse range of bioactivities including cytotoxicity, 1 insecticidal, 2 and antibacterial 3 as well as the exciting curative activity against malaria in animal models. 4,5 Since the first report of manzamine A, an additional 40 manzamine-type alkaloids have been reported from nine different sponge genera. 6,7 In our continuing search for manzamine-related alkaloids with significant activity against infectious diseases, we have identified several novel manzamine alkaloids from an Indonesian sponge, and herein we describe their structure determination and biological activity. *To whom correspondence should be addressed. Tel: (662) 915-5730. Fax: (662) 915-6975. mthamann@olemiss.edu. Supporting Information Available: Copies of 1 H and 13 C NMR spectra for all new compounds, HMQC spectra for 3, 5-7, HMBC spectra for 5-8, and X-ray data for 3. This material is available free of charge via the Internet at http://pubs.acs.org. (Table 1) includes aromatic proton resonances similar to those of manzamine E. 12 Spectral data of how 3 differs from manzamine E (2) includes the presence of 13 CH carbons (manzamine E has 12 CH carbons) and the absence of the low-field C-31 carbonyl carbon signal of manzamine E. In place of the carbonyl carbon compound 3 has a signal at 70.9 ppm, which correlates with a multiplet at 4.05 ppm in the HMQC spectrum. The presence of this new OH-functionality is confirmed by a number of long-range 1 H-13 C correlations H 2 -29 and H 2 -33 to C-31, Figure 1 HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript C-12, C-24, C-25, C-26, and C-34 of 3 were elucidated to be the same as those of manzamine E by NOESY data as well as comparable 13 C chemical shifts. In addition both compounds were isolated from the same sponge and possessed dextrorotation. The relative config...

BACKGROUND-The review presents the 2005-2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors' 1998-2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented.RESULTS-Anthelminthic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. SIGNIFICANCE-Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity and will probably result in novel therapeutic agents for the treatment of multiple disease categories. CONCLUSIONS-Marine

In addition to the previously reported bioactive kahalalide F six new peptides are described. Six of these, including kahalalide F, are cyclic depsipeptides, ranging from a C(31) tripeptide to a C(75) tridecapeptide isolated from a sacoglossan mollusk, Elysiarufescens. The mollusk feeds on a green alga, Bryopsis sp., which has also been shown to elaborate some of these peptides in smaller yields, in addition to an acyclic analog of F, kahalalide G. The bioassay results of antitumor, antiviral, antimalarial, and OI (activity against AIDS opportunistic infections) tests are reported.