Structure-activity studies of the pelorusides: new congeners and semi-synthetic analogues

Two new peloruside congeners (3 and 4) were isolated from wild and aquacultured collections of the New Zealand marine sponge Mycale hentscheli. Small-scale reactions on peloruside A (1) have been performed, which along with the isolation of 3 and 4, give further insight into the bioactive pharmacophore of 1.     

Marine natural products

This review covers the literature published in 2002 for marine natural products, with 579 citations (413 for the period January to December 2002) referring to compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds (677 for 2002), together with their relevant biological activities, source organisms and country of origin. Syntheses that lead to the revision of structures or stereochemistries have been included (114), including any first total syntheses of a marine natural product.     

Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules

Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to β-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in α,β-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates β-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.     

RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation

Eukaryotic initiation factor 4A (eIF4A) is a member of the DEAD-box family of putative RNA helicases whose members are involved in many aspects of RNA metabolism. eIF4A is thought to facilitate binding of 43S preinitiation complexes to mRNAs by unwinding secondary structures present in the 5' untranslated region. Pateamine A, a small-molecule inhibitor of translation initiation, acts in an unusual manner by stimulating eIF4A activity. Herein, we report the elucidation of pateamine's mode of action. We demonstrate that Pateamine A is a chemical inducer of dimerization that forces an engagement between eIF4A and RNA and prevents eIF4A from participating in the ribosome-recruitment step of translation initiation.     

Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

Laulimalide and peloruside A are microtubule‐stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X‐ray crystallography it is shown that laulimalide and peloruside A bind to a unique non‐taxane site on β‐tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane‐site M‐loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M‐loop of β‐tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.     

Natural Products from Tongan Marine Organisms

The islands of the South Pacific Ocean have been in the limelight for natural product biodiscovery, due to their unique and pristine tropical waters and environment. The Kingdom of Tonga is an archipelago in the central Indo-Pacific Ocean, consisting of 176 islands, 36 of which are inhabited, flourishing with a rich diversity of flora and fauna. Many unique natural products with interesting bioactivities have been reported from Indo-Pacific marine sponges and other invertebrate phyla; however, there have not been any reviews published to date specifically regarding natural products from Tongan marine organisms. This review covers both known and new/novel Marine Natural Products (MNPs) and their biological activities reported from organisms collected within Tongan territorial waters up to December 2020, and includes 109 MNPs in total, the majority from the phylum Porifera. The significant biological activity of these metabolites was dominated by cytotoxicity and, by reviewing these natural products, it is apparent that the bulk of the new and interesting biologically active compounds were from organisms collected from one particular island, emphasizing the geographic variability in the chemistry between these organisms collected at different locations.     

Marine natural products

This review covers the literature published in 2001 for marine natural products, with 497 citations (373 for the period January to December 2001) and includes 793 compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds and new stereochemical assignments (683 for 2001), together with relevant biological activities, source organisms and country of origin. Syntheses that confirm or revise structures or stereochemistries have been included (95), including any first total synthesis of a marine natural product.     

Molecular dynamics simulations of the enzyme Catechol-O-Methyltransferase: methodological issues1

Results from extensive 70 ns all-atom molecular dynamics simulations of catechol-O-methyltransferase (COMT) enzyme are reported. The simulations were performed with explicit TIP3P water and Mg^2?+ ions. Four different crystal structures of COMT, with and without different ligands, were used. These simulations are among the most extensive of their kind and as such served as a stability test for such simulations. On the methodological side we found that the initial energy minimization procedure may be a crucial step: particular hydrogen bonds may break, and this can initiate an irreversible loss of protein structure that becomes observable in longer time scales of the order of tens of nanoseconds. This has important implications for both molecular dynamics and quantum mechanics–molecular mechanics simulations.     

Geometric equilibrium distributions for queues with interactive batch departures

Gelenbe et al. [1, 2] consider single server Jackson networks of queues which contain both positive and negative customers. A negative customer arriving to a nonempty queue causes the number of customers in that queue to decrease by one, and has no effect on an empty queue, whereas a positive customer arriving at a queue will always increase the queue length by one. Gelenbe et al. show that a geometric product form equilibrium distribution prevails for this network. Applications for these types of networks can be found in systems incorporating resource allocations and in the modelling of decision making algorithms, neural networks and communications protocols.In this paper we extend the results of [1, 2] by allowing customer arrivals to the network, or the transfer between queues of a single positive customer in the network to trigger the creation of a batch of negative customers at the destination queue. This causes the length of the queue to decrease by the size of the created batch or the size of the queue, whichever is the smallest. The probability of creating a batch of negative customers of a particular size due to the transfer of a positive customer can depend on both the source and destination queue.We give a criterion for the validity of a geometric product form equilibrium distribution for these extended networks. When such a distribution holds it satisfies partial balance equations which are enforced by the boundaries of the state space. Furthermore it will be shown that these partial balance equations relate to traffic equations for the throughputs of the individual queues.