discodermolide and dictyostatin

The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

Topics: Alkanes; Animals; Carbamates; Humans; Lactones; Macrolides; Pyrones; Structure-Activity Relationship

Initially isolated in trace quantities from deep-sea sponges, the structurally related polyketides discodermolide and dictyostatin share the same microtubule-stabilizing antimitotic mechanism as Taxol. Discodermolide has been the focus of intense research activity in order to develop a practical supply route, and these efforts ultimately allowed its large-scale synthesis and the initiation of clinical trials as a novel anticancer drug. Similarly, the re-isolation and synthesis of dictyostatin continues to stimulate the biological and chemical communities in their quest for the development of new chemotherapeutic agents. This comprehensive review chronicles the synthetic endeavours undertaken over the last 15 years towards the development and realization of practical chemical syntheses of discodermolide and, more recently, dictyostatin, focusing on the methods and strategies employed for achieving overall stereocontrol and key fragment unions, as well as the design and synthesis of novel hybrid structures.

Topics: Alkanes; Antineoplastic Agents; Carbamates; Lactones; Macrolides; Marine Biology; Molecular Structure; Pyrones

An overview of marine natural products synthesis during 2005 is provided. In a similar vein to earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.

Topics: Alkaloids; Alkanes; Biological Products; Carbamates; Ethers; Guanidine; Guanidines; Lactones; Macrolides; Marine Biology; Molecular Structure; Pyrones; Spiro Compounds

Natural products have been used as medicinal agents for many years. In addition, these compounds have served as the starting points for semisynthetic analogs with improved properties. This review highlights work on several classes of natural products and their derivatives, including both well established and emerging structural classes that are in, or nearing, clinical use for a variety of important indications.

Topics: Alkanes; Antifungal Agents; Carbamates; Epothilones; Erythromycin; Furans; Gram-Positive Bacteria; Lactones; Lipids; Macrolides; Models, Chemical; Pyrones; Structure-Activity Relationship; Taxoids

The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule-stabilizing anticancer agents dictyostatin, discodermolide, and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavors towards accessing novel discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl-ether derivatives, along with the first triple hybrids bearing the side-chain of taxol or taxotere attached through an ester linkage. Biological assays of the anti-proliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic discodermolide/dictyostatin hybrid 12 and its C9 methoxy derivative 38, accessible by an efficient total synthesis and with a similar biological profile to dictyostatin.

Topics: Alkanes; Antimitotic Agents; Antineoplastic Agents; Carbamates; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Pyrones

A hybrid library of the marine natural products dictyostatin and discodermolide, incorporating the taxol or taxotere side chains, were synthesised; preliminary biological evaluation in the PANC-1 cancer cell line revealed significant antiproliferative activity, demonstrating that a macrolide scaffold is an effective surrogate for the baccatin core of taxol.

Topics: Alkanes; Antineoplastic Agents; Carbamates; Cell Line, Tumor; Humans; Lactones; Macrolides; Microtubules; Paclitaxel; Pyrones; Tubulin Modulators

By employing a diverted total synthesis strategy with late-stage intermediates, 10,11-dihydrodictyostatin ( 5) was prepared and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the NCI/ADR Taxol-resistant cell line. This novel dictyostatin analogue was found to retain potent antimitotic activity, with a comparable profile to discodermolide and Taxol, functioning by microtubule stabilization and G2/M arrest. These SAR studies provide further insight into the interaction between dictyostatin ( 1) and its tubulin target.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Humans; Macrolides; Molecular Conformation; Molecular Structure; Paclitaxel; Porifera; Stereoisomerism; Tubulin

By exploiting a Still-Gennari olefination of a common C11-C26 aldehyde with a C4-C10 or C1-C10 beta-ketophosphonate, three modified C2-C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis.

Topics: Alkanes; Animals; Antineoplastic Agents; Carbamates; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Molecular Structure; Paclitaxel; Porifera; Pyrones; Stereoisomerism; Structure-Activity Relationship; Tubulin

A potent dictyostatin-discodermolide hybrid was designed and synthesised; it showed enhanced cell growth inhibitory activity relative to discodermolide in four human cancer cell lines including the Taxol-resistant NCI/ADR-Res cell line.

Topics: Alkanes; Antineoplastic Agents; Biological Products; Carbamates; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Humans; Lactones; Macrolides; Paclitaxel; Pyrones

Compounds that bind to microtubules (MTs) and alter their dynamics are highly sought as a result of the clinical success of paclitaxel and docetaxel. The naturally occurring compound (-)-dictyostatin binds to MTs, causes cell cycle arrest in G(2)/M at nanomolar concentrations, and retains antiproliferative activity in paclitaxel-resistant cell lines, making dictyostatin an attractive candidate for development as an antineoplastic agent. In this study, we examined a series of dictyostatin analogs to probe biological and biochemical structure-activity relationships. We used a high-content multiparameter fluorescence-based cellular assay for MT morphology, chromatin condensation, mitotic arrest, and cellular toxicity to identify regions of dictyostatin that were essential for biological activity. Four analogs (6-epi-dictyostatin, 7-epi-dictyostatin, 16-normethyldictyostatin, and 15Z,16-normethyldictyostatin) retained low nanomolar activity in the cell-based assay and were chosen for analyses with isolated tubulin. All four compounds were potent inducers of MT assembly. Equilibrium binding constant (K(i)) determinations using [(14)C]epothilone B, which has a 3-fold higher affinity for the taxoid binding site than paclitaxel, indicated that 6-epi-dictyostatin and 7-epi-dictyostatin displaced [(14)C]epothilone B with K(i) values of 480 and 930 nM, respectively. 16-Normethyldictyostatin and 15Z,16-normethyldictyostatin had reduced affinity (K(i) values of 4.55 and 4.47 muM, respectively), consistent with previous reports showing that C16-normethyldictyostatin loses potency in paclitaxel-resistant cell lines that have a Phe270-to-Val mutation in the taxoid binding site of beta-tubulin. Finally, we developed a set of quantitative structure-activity relationship equations correlating structures with antiproliferative activity. The equations accurately predicted biological activity and will help in the design of future analogs.

Topics: Alkanes; Animals; Benzimidazoles; Binding Sites; Brain Chemistry; Carbamates; Carcinoma; Cattle; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Epothilones; Female; Fluorescein-5-isothiocyanate; Fluorescent Antibody Technique, Indirect; Fluorescent Dyes; G2 Phase; HeLa Cells; Histones; Humans; Kinetics; Lactones; Macrolides; Microtubules; Molecular Structure; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Protein Binding; Pyrones; Quantitative Structure-Activity Relationship; Radioligand Assay; Tubulin; Tubulin Modulators

A protocol based on a combination of NMR experimental data with molecular mechanics calculations and docking procedures has been employed to determine the microtubule-bound conformation of two microtubule-stabilizing agents, discodermolide (DDM) and dictyostatin (DCT). The data indicate that tubulin in assembled microtubules recognizes DDM through a conformational selection process, with minor changes in the molecular skeleton between the major conformer in water solution and that bound to assembled microtubules. For DCT, the deduced bound geometry presents some key conformation differences around certain torsion angles, with respect to the major conformer in solution, and still displays mobility even when bound. The bound conformer of DCT resembles that of DDM and provides very similar contacts with the receptor. Competition experiments indicate that both molecules compete with the taxane-binding site. A model of the binding mode of DDM and DCT to tubulin is proposed.

Topics: Alkanes; Carbamates; Computer Simulation; Lactones; Macrolides; Magnetic Resonance Spectroscopy; Microtubules; Molecular Conformation; Pyrones; Reference Standards; Reproducibility of Results; Solutions; Water

Novel analogues of the microtubule-stabilising agent dictyostatin were designed using existing SAR information from the structurally related discodermolide, synthesised by a late-stage diversification strategy and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including those known to exhibit Taxol-resistance (AsPC-1, DLD-1, PANC-1, NCI/ADR).

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Macrolides; Models, Chemical; Molecular Conformation; Paclitaxel; Structure-Activity Relationship

The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16-dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16-dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents.

Topics: Animals; Antineoplastic Agents; Binding, Competitive; Cattle; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Macrolides; Microtubules; Stereoisomerism; Structure-Activity Relationship; Tubulin

A 22-membered macrocyclic discodermolide/dictyostatin hybrid has been designed and synthesised; biological evaluation against a range of human cancer cell lines revealed significant levels of growth inhibition.

Topics: Alkanes; Carbamates; Cell Line, Tumor; Cell Proliferation; Humans; Lactones; Macrocyclic Compounds; Macrolides; Models, Molecular; Molecular Structure; Pyrones

[reaction: see text] An esterification/ring-closing metathesis approach to dictyostatin and discodermolide is introduced. The approach provides for facile fragment coupling of two main segments of these natural products at the C10-C11 alkene with high to complete Z-selectivity.

Topics: Alkanes; Carbamates; Esters; Indicators and Reagents; Lactones; Macrolides; Molecular Conformation; Oxidation-Reduction; Pyrones; Structure-Activity Relationship

(-)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to cause cells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogous to those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin more rapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener, (+)-discodermolide (Isbrucker et al. (2003), Biochem. Pharmacol. 65, 75-82). We used synthetic (-)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activity of dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide, dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxel due to beta-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailed comparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstrated that the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolide to microtubules more potently than any other compound examined, and dictyostatin and discodermolide had equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules. These results are consistent with the idea that the macrocyclic structure of dictyostatin represents the template for the bioactive conformation of discodermolide.

Topics: Alkanes; Antineoplastic Agents; Binding Sites; Carbamates; Cell Line, Tumor; Cell Proliferation; Humans; Lactones; Macrolides; Microscopy, Fluorescence; Microtubules; Paclitaxel; Pyrones; Tubulin

[structure: see text] Two hybrid analogues of discodermolide and dictyostatin (3, 26) have been designed and synthesized. These are the first macrocyclic analogues of discodermolide and biological activities were evaluated and compared with linear discodermolide analogues.

Topics: Alkanes; Antineoplastic Agents; Breast Neoplasms; Carbamates; Female; Humans; Lactones; Macrolides; Ovarian Neoplasms; Pyrones; Tumor Cells, Cultured