Antimitotic alkaloid

Blood and circulatory system. All animals need to transport nutrients, hormones, ions, signal compounds, and gas between the different oigans of the body, which is achieved by higher animals through blood in the circulatory system. Inhibitors of the driving force for this process, the heart muscle, have already been discussed. However, the synthesis of red blood cells is also vulnerable and can be inhibited by antimitotic alkaloids such as vinblastine or colchicine (312). 

The stereoselective total synthesis of antimitotic alkaloid (+)-lycoricidine was accomplished by S. Ogawa and coworkers by utilizing the catalytic version of the Type II Ferrier rearrangement for the synthesis of the optically active... 

In the course of total syntheses of the antimitotic alkaloid ( + )-colchicine and its biologically active analog 12 the rearrangement of 9 and 11 to tropolone methyl ether 10 and 12, respectively, assisted by ten equivalents of l,8-diazabicyclo[5.4.0]undec-7-ene, was used as the key step. ... 

A synthesis of both of the antimitotic alkaloids (-)-colchicine (134) and its isomer (-)-isocolchicine was successively completed [ 124] using the synthetic... 

In addition, the alkaloid colchicine (from Colchicum autumnale) blocks tubulin polymerization by binding to heterodimeric (3-tubulin between amino acids 239 and 254. Since it inhibits the MT-dependent migration of granulocytes into areas of inflammation and their MT-dependent release of proinflammatory agents, it is used to treat attacks of gout. Its antimitotic effect in the gastrointestinal system induces diarrhoea. Nocodazole competes for the binding site of colchicine and has similar effects on heterodimeric (3-tubulin. 

Finally, the report by Angenot et al. of an exceptional increase of antimitotic activity in strychnopentamine (104) caused by the presence of a supplementary pyrrolidine ring, is worth noting (199). Chemists might use this fact as an reason to promote interesting new syntheses of pyrrolidine alkaloids or creation of unnatural molecules containing pyrrolidine. 

Kruczynski A, Barret JM, Etievant C, Colpaert F, Fahy J, Hill BT. (1998) Antimitotic and tnbnlininteracting properties of vinflnnine, a novel flnori-nated Vinca alkaloid. Biochem Pharmacol 55 635-648. 

Dividing cells in culture exposed to vinblastine or vincristine are arrested from further growth during mitosis (12,13). In fact, the antimitotic effects of this class of compounds is ubiquitous. These effects are observed at relatively low concentrations (<1 iM), and are reversible when drug is removed from the media prior to lysis of the arrested cells. The concentration of drug required to elicit an antimitotic effect is usually comparable to that required to produce a cytotoxic effect in the same cell type (14,15). Originally, this type of analysis was exceedingly laborious, but the introduction of laser- and computer-based fluoresence activated cell sorters (FACS) has rendered this type of analysis routine. Nevertheless, a cytotoxic, non-cell cycle-specific bisindole alkaloid has yet to be discovered. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Antimitotic agents Vinca alkaloids Lung adenocarcinoma... 

Leclerq, J., Quetin, J., De Pauw-Gillet, M.-CL, Bassleer, R. and Angenot, L. 1987. Antimitotic and cytotoxic activities of guattegaumerine, a bisbenzylisoquinoline alkaloid. Planta Medica, 116-117. 

Figure 4.48 Antimitotic drugs derived from Vinca dimer alkaloids.

The best known drugs acting as antimitotics are the vinca alkaloids, vincristine (7.90) and vinblastine (7.91). They are very complex indole derivatives that nevertheless have been synthesized. Both are quite effective in various leukemias and in Hodgkin s lymphoma, but show considerable neurotoxicity. Vinblastine and vincristine bind specifically to the microtubular protein tubulin in dimeric form, precipitating depolymerization of the microtubules and functionally acting as a mitotic poison. Vinorelbine (7.92) is a semisynthetic vinca alkaloid functionally identical to vinblastine. 

Manzo E, van Soest R, Matainaho L, Roberge M, Andersen RJ (2003) Ceratamines A and B, Antimitotic Heterocyclic Alkaloids Isolated from the Marine Sponge Pseudoceratina sp. Collected in Papua New Guinea. Org Lett 5 4591... 

Alkaloids are nitrogen-based compounds frequently found in plants. Plant alkaloids that are used in treating cancer in humans include traditional agents, such as vincristine and vinblastine, and newer agents, such as vinorelbine, paclitaxel, and docetaxel (Table 36-4). These agents are also known as antimitotic drugs be-... 

Narciclasine (215) is an antitumor agent which exerts an antimitotic effect during metaphase by immediately terminating protein synthesis in eukaryotic cells at the step of peptide bond formation (97,101,141,142), apparently by interaction with the ansiomycin area of the ribosomal peptidyl transferase center (142). The alkaloid has also been found to inhibit HeLa cell growth and to stabilize HeLa cell polysomes in vivo (97). Although DNA synthesis was retarded by narciclasine, RNA synthesis was practically unaffected (97,142). Sev-... 

The antimitotic lactam narciclasine (376) is widely distributed in Amaryllidaceae plants. It seems, however, nonassociated apparently with any particular alkaloid, the only chemotaxonomic peculiarity being its absence in plants usually containing alkaloids possessing the ( - )-crinane skeleton (101). 

Bai, R.L., G.R. Pettit, and E. Hamel. 1990. Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and Vinca alkaloid sites./. Biol. Chem. 

The area covered by natural products chemistry is boundless as it deals with nature itself. There is literally no limit to the topics to be dealt with. This volume 29 continues the tradition of supplying us with superb review articles written by experts. The articles in this volume deal with the screening, isolation, structure, synthesis, biosynthesis, and pharmacology of plant and microbial natural products that exhibit antimitotic, cancer chemotherapeutic, enzyme inhibitory, antiinflammatory, antibiotic and molting hormone activities. The compound types also cover a huge range of natural products, i.e., polyketides, terpenoids, sugars, alkaloids, proteins, and enzymes. 

Taxine alkaloids are complex polycyclic compounds in which N is present but not as an integral part of a ring. The taxines are found in Taxus (yew) species (Taxaceae). Taxine A (C61 CIO ] C6-0-C0-CH(0H)-CH(N(CH3)2)-Phe) is substantially responsible for yew toxicity. The related polycyclic amide taxol (paclitaxel) and the closely related docetaxel are tubulin-binding, antimitotic cytotoxics that are used clinically as anticancer drugs. A variety of taxines have been isolated from Taxus species. 

Another group of alkaloids with antimitotic properties are the bisindole alkaloids, such as vinblastine and vincristine, which have been isolated from Catharanthus roseus (Apocynaceae). These alkaloids also bind to tubulin (312). Both alkaloids are very toxic, but are nevertheless important drugs for the treatment of some leukemias. 

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