Synthesis of amphidinolide Y precursors

Mola, Laura; Olivella, Anna; Urpı́, Fèlix; Vilarrasa, Jaume

doi:10.1016/j.tetlet.2013.12.047

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…In this context, over the past two decades our research group has worked on the total synthesis of bioactive macrolide-like natural products, such as fluvirucins [ 3 , 4 ]; amphidinolides X [ 5 ], Y [ 6 ], K [ 7 ], E [ 8 ] and B2 [ 9 ]; and palmerolide A [ 10 ]. We performed docking calculations and collaborated with biochemists, chiefly with the aims of elucidating the mechanisms of action of some cytotoxic macrolides [ 11 , 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

2017

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The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

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Section: Introductionmentioning

confidence: 99%

The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

2017

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“…Because the cocrystal structures of tubulin protofilaments with 1 and protofilaments with 2 , very recently published, showed the M-loop folded as an α-helix (Figure ), we have subjected our tetramer model to a metadynamics simulation with Desmond. , To the best of our knowledge, after an extensive search through SciFinder and SciFinder n , metadynamics simulations of 1 or 2 (interacting with β1) have not been previously reported. There are no metadynamics studies of other antimitotic macrolides, the total syntheses of which are a long-standing research line of the senior author. − There is only one metadynamics study that involves the microtubule-destabilizing agent combretastatin . Two works on the energy profiles of other antimitotic agents have also been reported. , …”

Section: Results and Discussionmentioning

confidence: 99%

“…The events, when ligands 1 or 2 approach the binding site, can be represented as in Figure 19 (a cartoon). We are conscious that the results are approximate because of the unavoidable simplifications, including the use of tetramers or hexamers instead of large microtubule portions (MD calculations that are practically infeasible at present), but they pave the way for future computational studies, in which we plan to examine more deeply the known experimental synergy between some tax site - and ext site -binding antimitotic drugs, 43−46 in the light of the cryo-EM studies of Kellogg et al 7 and of the calculations disclosed here. In our MD simulations on tetramer and hexamer models, adding 1 and 3a or 2 and 3a , both types of drugs are predicted to favor mainly the contacts between the M-loop of one β-tubulin with the H1–B2 loop of the neighboring β-tubulin, as expected.…”

Section: Discussionmentioning

confidence: 99%

Further Insight into the Interactions of the Cytotoxic Macrolides Laulimalide and Peloruside A with Their Common Binding Site

2018

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The binding site of the macrolides laulimalide and peloruside A, which is different from that of the clinically useful drugs paclitaxel/taxol and ixabepilone ( tax site ), is known to be between two adjacent β-tubulin units ( ext site ). Here, we report our study of the binding of these molecules to an α1β1/α2β2-tubulin “tetramer” model. AutoDock 4.2.6//AutoDock Vina dockings predicted that the affinities of laulimalide and peloruside A for the tax site are quite similar to those for the ext site . However, molecular dynamics (MD) simulations indicated that only when these two ligands are located at the ext site , there are contacts that help stabilize the system, favoring the β1/β2 interactions. The binding affinity of laulimalide for this site is stronger than that of peloruside A, but this is compensated for by additional β1/β2 contacts that are induced by peloruside A. MD studies also suggested that epothilones at the tax site and either laulimalide or peloruside A at the ext site cause similar stabilizing effects (mainly linking the M-loop of β1 and loop H1–B2 of β2). In a “hexamer” model (3 units of αβ-tubulin), the effects are confirmed. Metadynamics simulations of laulimalide and peloruside A, which are reported for the first time, suggest that peloruside A produces a stronger change in the M-loop, which explains the stabilization of the β1/β2 interaction.

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“…Examples of the total synthesis of important natural compounds will be presented and discussed in a comprehensive way. It should be emphasized that the examples discussed are the authors' selection; other important natural scaffolds also use the Wittig reaction as a key step, for example dienamines, 2 H ‐azirine, sphingolipids, macrolides, and pyrenes, but these were not discussed herein.…”

Section: Total Synthesis Of Natural Heterocyclic Compoundsmentioning

confidence: 99%

Applications of the Wittig Reaction on the Synthesis of Natural and Natural‐Analogue Heterocyclic Compounds

2018

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More than sixty years after its discovery, the Wittig reaction still is a powerful tool to create carbon–carbon double bonds. The large diversity of high‐yielding and stereoselective reactions that can be achieved, even for highly functionalized molecules, is presented, demonstrating that the Wittig reaction is an efficient and attractive strategy in synthetic organic chemistry. The principles of the reaction will be briefly presented and discussed, but the focus will be on the most recent reports using this reaction in the synthesis of heterocyclic compounds. A comprehensive discussion on its application in the total synthesis of natural products and in the synthesis of natural analogues will be presented. Emphasis will be given to important organic molecules that present interesting biological activities. The purpose of this short review is to highlight the advances in this general area by presenting such newer applications in organic synthesis and eventually guide future researchers.

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Synthesis of amphidinolide Y precursors

Cited by 8 publications

References 27 publications

The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

Further Insight into the Interactions of the Cytotoxic Macrolides Laulimalide and Peloruside A with Their Common Binding Site

Applications of the Wittig Reaction on the Synthesis of Natural and Natural‐Analogue Heterocyclic Compounds

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