Jiangnan Peng

Structure and absolute configuration of karlotoxin-2, an ichthyotoxin from the marine dinoflagellate Karlodinium veneficum.

In an attempt to determine the cause of repeated fish kills in an estuarine aquaculture facility in Maryland, a toxin with hemolytic, cytotoxic, and ichthyotoxic properties, designated as karlotoxin-2 (KmTx2), was isolated from Karlodinium veneficum. The structure of KmTx2 was elucidated by means of detailed ID and 2D NMR spectra, including 2D INADEQUATE. The relative and absolute configurations of KmTx2 were determined using J-based configuration analysis and comparison of its degradation products with synthetic controls.

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.

Novel sesquiterpenes and a lactone from the Jamaican sponge Myrmekioderma styx

Abstract Two novel sesquiterpenes, styxone A ( 1 ) and styxone B ( 2 ), and a novel lactone, styxlactone ( 3 ), were isolated from the Jamaican sponge Myrmekioderma styx . Their structures were elucidated by detailed 1 H, 13 C and 2D NMR data and the absolute stereochemistry of styxone A and B was determined by CD spectra. Styxone A represents a novel sesquiterpene skeleton. ( S )-(+)-Curcuphenol ( 4 ), ( S )-(+)-curcudiol ( 5 ), and abolene ( 6 ) were also isolated. An activity enhancement by cyanthiwigin B ( 7 ) to curcuphenol was observed in the antimicrobial assays when the two compounds were administered together.

Potent Taccalonolides, AF and AJ, Inform Significant Structure–Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers

The taccalonolides are a class of microtubule stabilizing agents isolated from plants of the genus Tacca. In efforts to define their structure-activity relationships, we isolated five new taccalonolides, AC-AF and H2, from one fraction of an ethanol extract of Tacca plantaginea. The structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HR-ESI-MS. Taccalonolide AJ, an epoxidation product of taccalonolide B, was generated by semisynthesis. Five of these taccalonolides demonstrated cellular microtubule-stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ exhibiting the highest potency with an IC(50) value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to >50 μM, for the first time provides the opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays, taccalonolides AF and AJ stimulated the polymerization of purified tubulin, an activity that had not previously been observed for taccalonolides A and B, providing the first evidence that this class of microtubule stabilizers can interact directly with tubulin/microtubules. Taccalonolides AF and AJ were able to enhance tubulin polymerization to the same extent as paclitaxel but exhibited a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site. The potencies of taccalonolides AF and AJ and their direct interaction with tubulin, together with the previous excellent in vivo antitumor activity of this class, reveal the potential of the taccalonolides as new anticancer agents.

Identification and biological activities of new taccalonolide microtubule stabilizers.

The taccalonolides are a unique class of microtubule stabilizers that do not bind directly to tubulin. Three new taccalonolides, Z, AA, and AB, along with two known compounds, taccalonolides R and T, were isolated from Tacca chantrieri and Tacca integrifolia. Taccalonolide structures were determined by 1D and 2D NMR methods. The biological activities of the new taccalonolides, as well as taccalonolides A, B, E, N, R, and T, were evaluated. All nine taccalonolides display microtubule stabilizing activity, but profound differences in antiproliferative potencies were noted, with IC(50) values ranging from the low nanomolar range for taccalonolide AA (32 nM) to the low micromolar range for taccalonolide R (13 μM). These studies demonstrate that diverse taccalonolides possess microtubule stabilizing properties and that significant structure-activity relationships exist. In vivo antitumor evaluations of taccalonolides A, E, and N show that each of these molecules has in vivo antitumor activity.

Taccalonolide Binding to Tubulin Imparts Microtubule Stability and Potent In Vivo Activity

The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. In addition, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide, or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of β-tubulin containing the cyclostreptin-binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind to tubulin, consistent with the distinct effects of the taccalonolides as compared with other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site.

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.

Polyketide-peroxides from a Species of Jamaican Plakortis (Porifera: Demospongiae)

A new cyclic peroxide plakortisinic acid (1), and a new ketone derivative (2), in addition to six known compounds, an α,β-unsaturated ester (3), plakortide N (4), plakortide F (5) and its free acid (6), plakortone D (7), and a furan-containing molecule (8), were isolated from a species of Plakortis from Jamaica. The structures were elucidated by interpretation of 1D and 2D NMR spectra, and mass spectrometry data and by comparison with data from the literature. Comparison between experimental and calculated optical rotations allowed the assignment of absolute configuration of 1 and 2. The isolated compounds have been evaluated for their antimicrobial, antimalarial, anticancer, anti-Mtb, and anti HIV-1 activity.

The marine bromotyrosine derivatives.

Publisher Summary This chapter discusses the isolation, structure, physicochemical and spectral data of all bromotyrosine derivatives isolated from marine organisms. The biosynthesis, total synthesis, and bioactivity of the bromotyrosine derivatives are also discussed followed by cyclopeptides containing halogenated tyrosine units. The bromotyrosine derivatives are divided into six categories: simple bromotyrosine derivatives, spirocyclohexadienylisoxazolines, spirooxepinisoxazolines, oximes, bastadins, and other structural classes. The simple bromotyrosine derivatives are products of one bromotyrosine undergoing degradation, reduction, hydroxylation, alkylation, or esterification with simple functional groups. In spirocyclohexadienylisoxazoline bromotyrosine derivatives, one or two bromotyrosine units are transformed into a spirocyclohexadienylisoxazoline undergoing an arene oxide biosynthetic pathway. This class of alkaloids generally consists of one to three bromotyrosinederived units, as well as other functional groups, such as histamine. Bromotyrosine alkaloids provide a unique diversity in chemical structure and in bioactivity. As the first bromotyrosine derivative, the dienone, was isolated as an antibiotic, a large number of bromotyrosine derivatives have been found to have diverse activities, which include antibacterial, antifungal, anticancer, antiviral, antifouling, etc. The majority of the dibromotyrosine-derived natural products from Verongida have been reported to possess significant antimicrobial and cytotoxic activity. The presence of antibacterial compounds in marine sponges has been reported as a general phenomenon, and has been suggested to reflect a defensive strategy of these sedentary, filter-feeding animals.

Evelynin, a Cytotoxic Benzoquinone-Type retro-Dihydrochalcone from Tacca chantrieri

A new benzoquinone-type retro-dihydrochalcone, named evelynin, was isolated from the roots and rhizomes of Tacca chantrieri. The structure was elucidated on the basis of the analysis of spectroscopic data and confirmed by a simple one-step total synthesis. Evelynin exhibited cytotoxicity against four human cancer cell lines, MDA-MB-435 melanoma, MDA-MB-231 breast, PC-3 prostate, and HeLa cervical carcinoma cells, with IC(50) values of 4.1, 3.9, 4.7, and 6.3 μM, respectively.