discodermolide and Neoplasms

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Products; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship

Natural compounds derived from marine organisms have shown a wide variety of anti-tumor effects and a lot of attention has been drawn to further development of the isolated compounds. A vast quantity of individual chemical structures from different organisms has shown a variety of apoptosis inducing mechanisms in a variety of tumor cells. The bis-steroidal cephalostatin 1 for example, induces apoptosis via activation of caspases whereas the polyketide discodermolide inhibits cell growth by binding to and stabilizing microtubule and salisporamide A, the product of an actinobacterial strain, is an inhibitor of the proteasome. This great variety of mechanisms of action can help to overcome the multitude of resistances exhibited by different tumor specimens. Products from marine organisms and their synthetic derivates are therefore an important source for new therapeutics for single agent or combined therapy with other chemotherapeutics to support the struggle against cancer.

Topics: Alkaloids; Alkanes; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Aquatic Organisms; Biological Products; Bryostatins; Carbamates; Cell Proliferation; Depsipeptides; Dioxoles; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Microtubules; Models, Chemical; Neoplasms; Phenanthrolines; Phenazines; Proteasome Endopeptidase Complex; Pyrones; Pyrroles; Quinolines; Spiro Compounds; Steroids; Tetrahydroisoquinolines; Thiazoles; Trabectedin

Microtubule stabilization by chemotherapy is a powerful weapon in the war against cancer. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell or lead to its death via apoptosis. Taxol, the first microtubule stabilizing drug to be identified, has been utilized successfully in the treatment of solid tumors for two decades. Several features, however, make this drug less than ideal, and the search for next generation stabilizing drugs with increased efficacy has been intense and fruitful. Microtubule stabilizing agents (MSAs), including the taxanes, the epothilones, discodermolide, laulimalide, and eleutherobin, form an important and expanding family of chemotherapeutic agents. A strong understanding of their molecular signaling consequences is essential to their value, particularly in regard to their potential for combinatorial chemotherapy - the use of multiple agents to enhance the efficacy of cancer treatment. Here we present a critical review of research on the signaling mechanisms induced by MSAs, their relevance to apoptosis, and their potential for exploitation by combinatorial therapy.

Topics: Alkanes; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cyclooxygenase 2; Diterpenes; Epothilones; Humans; Inhibitor of Apoptosis Proteins; Interleukin-1; Interleukin-8; Lactones; Macrolides; MAP Kinase Kinase 1; MAP Kinase Signaling System; Maturation-Promoting Factor; Microtubule-Associated Proteins; Microtubules; Neoplasm Proteins; Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrones; Signal Transduction; Survivin; Taxoids; Tumor Suppressor Protein p53

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

The natural products kahalalide F, halichondrin B, and discodermolide are relatively large structures that were originally harvested from marine organisms. They are oxygen rich structures that, to varying degrees, should have the ability to bind iron (II or III) by Fe-O and/or Fe-N bonds. In this semi empirical study, the binding of these natural products to iron (II) is studied and the aqueous stability factor (ASF) is used to determine which bonding configuration is most stable. The energy, the complex charge (+1), the average Fe-O (or Fe-N) bond distances and the dipole moments are used to calculate the ASF. The ASF provides insight to which complex will be the most stable and water soluble, important for a medicinal application. The ability of a molecule with a more than six oxygen and/or nitrogen atoms to bind iron (hexavalent, octahedral) by shifting which six atoms (O/N) are bound to the iron qualifies it as a polarity adaptive molecule.

Topics: Alkanes; Animals; Antineoplastic Agents; Biological Products; Carbamates; Cell Line, Tumor; Chemical Phenomena; Computational Biology; Depsipeptides; Ethers, Cyclic; Humans; Inhibitory Concentration 50; Iron; Lactones; Macrolides; Models, Molecular; Molecular Conformation; Neoplasms; Oxygen; Pyrones; Siderophores; Structure-Activity Relationship