Karumanchi V. Rao

Structure-Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

12,34-Oxamanzamines, novel biocatalytic and natural products from manzamine producing Indo-Pacific sponges

ent-12,34-Oxamanzamines E (1) and F (2), as well as 12,34-oxamanzamine A (4) were isolated from three Indo-Pacific sponges and their structures were assigned on the basis of spectroscopic data. The biocatalytic transformation of ent-8-hydroxymanzamine A (3) to 2, using Nocardia sp. ATCC 21145 and Fusarium oxysporium ATCC 7601, has also been achieved. These compounds possess a novel ring system generated through a new ether bridge formed between carbons 12 and 34 of the typical manzamine structure. Ten heterotrophic bacterial isolates, including actinomycetes and α-proteobacteria, were isolated from one of these sponges in a preliminary effort to identify a possible microbial origin for these compounds. The potent activity of the manzamines against malaria and the AIDS OI pathogen, Mycobacterium tuberculosis, is also presented.

Secondary metabolites from three Florida sponges with antidepressant activity.

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.

Kahalalides V–Y Isolated from a Hawaiian Collection of the Sacoglossan Mollusk Elysia rufescens

Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-L-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an L configuration. Kahalalide Y (4) was found to have an L-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.

An analysis of the sponge Acanthostrongylophora igens' microbiome yields an actinomycete that produces the natural product manzamine A

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium (Micromonospora sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganisms microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time.

5-OHKF and NorKA, depsipeptides from a Hawaiian collection of Bryopsis pennata: binding properties for NorKA to the human neuropeptide Y Y1 receptor.

Two new cyclic depsipeptides, 5-OHKF (1) and norKA (2), together with the known congeners kahalalide F (3) and isokahalalide F ((4S)- methylhexanoic kahalalide F) (4) were isolated from the green alga Bryopsis pennata. The structures of the new compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis and mass spectrometric (ESIMS) data. The absolute configuration of each amino acid of 5-OHKF (1) and norKA (2) was determined by chemical degradation and Marfeys analysis. The biological activities of these two compounds are also reported.

The biocatalytic conversion of 8-hydroxymanzamine a to manzamine A

The selective dehydroxylation of 8-hydroxymanzamine A (1) to form manzamine A (2) can be completed by fermentation with Fusarium solani or Streptomyces seokies. This unique biocatalytic conversion is important due to the fact that manzamine A has more desirable biological activity when assayed in a murine model against malaria.

Terpenes from Eunicea laciniata and Plexaurella nutans

A new 7,8–epoxydolabella–3(E)–12(18)–diene (1), diterpenoid together with three known compounds were isolated from a Honduras gorgonian Eunicea laciniata. The relative stereochemistry of 1 was established by spectroscopic studies and the antiprotozoal and antimicrobial activities of dolabellane diterpenoids 2–4 are reported. Three known cadinane type sesquiterpenes were also isolated from Honduras gorgonian Plexaurella nutans.

7-Methyl-9-oxo-dec-7-eneoic acid from the Red Sea sponge Ircinia sp

An NMR and ultra-high resolution mass investigation of secondary metabolites from a Red Sea sponge Ircinia sp. led to the isolation and characterisation of a new ketone. The structure has been assigned on the basis of detailed spectroscopic analysis (1H, 13C, DEPT, COSY, HMQC and HMBC NMR spectra) as 7-methyl-9-oxo-dec-7-eneoic acid (1). Ultra-high resolution FTMS was utilised to facilitate the formulation and structure assignment because there was a broad and undetectable carbon signal in the NMR spectra.