Colchicine structure

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

The. structure.s of vinbla.stine, vincri.stine, colchicine, and taxol. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

The ER has a reticular morphology which provides a large surface area, which presumably is required for the synthesis and transport of proteins and lipids and for the storage of calcium. The ER is associated with microtubules, and the two are highly interdependent structures. Terasaki et al. (1986) found that when microtubules in the cell are depolymerized by colchicine, the ER network slowly retracts toward the center of the cell. If the microtubules are repolymerized, the ER network is restored to its original morphology, thereby suggesting that the MTs participate in the formation and maintenance of the ER. 

Experiment 7. Alkaloid colchicine binds tubulin in cell structures. 

Colchicine (6) was isolated by Pelletier and Caventou in 1820 and is the main alkaloid of the poisonous meadow saffron plant (Colchicum autum-nale L.) [12-16]. Following some considerable debate over colchicine s structure [17-20] and its successful synthesis [21-26], colchicine was found to bind to tubulin at what is referred to as the colchicine binding site [1,27]. 

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

Metaphase Analysis. Metaphase analysis can be performed in any tissue with actively dividing cells, but bone marrow is the tissue most often examined. Cells are treated with a test compound and are arrested in metaphase by the administration of colcemid or colchicine at various sampling times after treatment. Preparations are examined for structural chromosome damage. Because the bone marrow has a good blood supply, the cells should be exposed to the test compound or its metabolites in the peripheral blood supply. Additionally, these cells are sensitive to S-dependent and S-independent mutagens (Topham et al., 1983). 

The role of microtubules in neutrophil function can be investigated using agents such as colchicine, colcemid, vinblastine and vincristine, which disrupt these structures. Stimulation of neutrophils with chemotactic agents causes a rapid and transient assembly of microtubules, but this assembly does not affect chemotaxis. Similarly, cytoplasts (neutrophils devoid of nu-... 

Vesicular transport of bile acids has not been demonstrated under normal conditions, shown by using isolated rat hepatocyte couplets and fluorescently labelled bile acids. In these experiments confocal microscopy found no evidence of sequestering into clusters and colchicine disruption of microtubular function did not affect bile-acid transport. This makes it unlikely that vesicle transport plays a role and it is now believed that bile acids traverse the hepatocyte by diffusion through the cytosol while bound to soluble proteins. It is worth considering the caveat that fluorescently labelled bile acids, while very useful tools, do differ structurally from endogenous bile acids with increased hydro-phobicity leading to greater retention by cells. ... 

The tropolone alkaloid of Liliaceae species, colchicine, is transformed by acetylation, alkaline cyclization, and dehydration into the tetracyclic pyrrolotropone acetyl anhydrocolchicine [77TL2977 83AX(C)1709]. When the dicarboxylic acid anhydride groups of puberulonic and stipitatonic acids (metabolites of Penicillium species) condense with o-phenylenediamine, another tetracyclic pyrrolotropone structure is formed (51JCS1139 59JCS2847). 

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). 

Woodward then moved across town in Cambridge to devote a year of postgraduate study at Harvard University. At the end of that year, he accepted an appointment to the Harvard chemistry faculty, a post he held for most of the rest of his life. One of his great interests at Harvard was the synthesis of large, complex molecules, the first of which was quinine in 1944. He followed that work with the elucidation of other molecular structures and the development of synthetic methods for each. Included among these molecules were penicillin (1945), patulin (1948), cholesterol and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid (1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin C (1965), and vitamin (1971). 

A variety of cell lines, strains, or primary cell cultures, including human cells, may be used (e.g., Chinese hamster fibroblasts, human or other mammalian peripheral blood lymphocytes). Cell cultures are exposed to the test substance both with and without metabolic activation and at predetermined intervals after exposure, they are treated with a metaphase-arresting substance (e.g., colchicine), harvested, stained, and metaphase cells are analyzed microscopically for the presence of structural chromosome aberrations. At least three concentrations should be used. 

Although NSAIDs are now the first-line drugs for acute gout, colchicine was the primary treatment for many years. Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. Its structure is shown in Figure 36-6. 

Despite the simple structure of a glucopyranoside linked to a colchicine or thio-colchicine moiety, subtilisin-catalyzed acylation of colchicoside and thiocolchico-side still represents the only example of regioselective esterification of alkaloid... 

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