Colchicin

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

With the introduction of improved analytical techniques, starting around 1817, the evaluation of dmgs began and, over a span of about 10 years, strychnine (13, R = H), emetine (14), bmcine (13, R = OCH3), piperine (15), caffeine (16), quinine (17, R = OCH3), colchicine (4), cinchonidine (17,... 

The influences of herbicides on cell division fall into two classes, ie, dismption of the mitotic sequence and inhibition of mitotic entry from interphase (G, S, G2). If ceU-cycle analyses indicate increases in abnormal mitotic figures, combined with decreases in one or more of the normal mitotic stages, the effect is upon mitosis. Mitotic effects usually involve the microtubules of the spindle apparatus in the form of spindle depolymerization, blocked tubulin synthesis, or inhibited microtubule polymerization (163). Alkaloids such as colchicine [64-86-8J,viahla.stiae [865-21-4] and vincristine [57-22-7] dismpt microtubule function (164). Colchicine prevents microtubule formation and promotes disassembly of those already present. Vinblastine and vincristine also bind to free tubulin molecules, precipitating crystalline tubulin in the cytoplasm. The capacities of these dmgs to interfere with mitotic spindles, blocking cell division, makes them useful in cancer treatment. 

DCPA inhibits the growth of grass species by dismpting the mitotic sequence, probably at entry (190). DCPA influences spindle formation and function (181) and causes root-tip swelling (182) and britde shoot tissue (191). It has been reported that DCPA, like colchicine and vinblastine, attests mitosis at prometaphase and is associated with formation of polymorphic nuclei after mitotic arrest (192). Pronamide also inhibits root growth by dismpting the mitotic sequence in a manner similar to the effect of colchicine and the dinitroanilines (193,194). Cinmethylin and bensuhde prevent mitotic entry by unknown mechanisms (194). 

The isothiazole ring was used as a template in Woodward s brilliant total synthesis of colchicine (237 Scheme 42) (72AHC(l4)l). 

Coformycin, 2 -deoxy—see Pentostatin Colchicine synthesis, 1, 472 isothiazoles in, 6, 174 Collins reagent as oxidizing agent, 2, 170 Colour... 

Internal protection, used by van Tamelen in a synthesis of colchicine, may< in... 

Coenzyme Qo (2,3-Dimethoxy-5-methyl-l,4-benzoquinone, 3,4-dimethoxy-2,5-tolu-quinone, fumigatin methyl ether), colchicine and colchicoside see entries in Chapter 6. 

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). ... 

Colchicine (hRf 35 — 40) appeared as yellow fluorescent zone on a dark background in long-wavelength UV light (A = 365 nm). The detection limit was 10 ng per chromatogram zone. 

Fig. 1 Fluorescence scan of a chromatogram track with an extract of Colchicum autumnale (A) and of a reference track (B, 1 tg colchicine) start (1), colchicine (2).

Commercial colchicine usually consists of yellow flakes or powder, or crystals containing chloroform of crystallisation. It can be crystallised from water as a trihydrate, or from ethyl acetate (Clewer et al. ) forming soft, pale yellow needles, m.p. 155-7°, — 120-8° (CHClg) or... 

According to Grewe, colchicine on exposure to ultra-violet light changes to an isomeride, needles, m.p. 220°, which he has named lumieolehieine. 

The location of a methoxyl group at position 4 in ring A was proved indirectly by Windaus, whence it follows that the three vicinal methoxy groups in that ring must occupy positions 2-, 3- and 4-. The positions of all four methoxyl groups in colchicine were later clearly settled by Barton, Cook and Loudon (p. 653). 

Cook has suggested that colchicine itself may contain the 7-membered ring B and Dewar has proposed for the alkaloid formula (XV) with (XVfl) as a resonance form, mainly on the ground that the third ring (C) in colchicine resembles in some of its reactions, stipitatic acid and presents similar difficulty in interpretation of experimental results. 

Lettre and Fernholz have tested a series of colchicine derivatives, including a group of alkylcolchiceines, on experimentally induced tumours all proved to be less potent than the parent alkaloid. A -Acetyl-j3-p-anisyl-y-(3 4 5-trimethoxyphenyl)-propylamine,... 

Much of the biological work with colchicine in recent years has lain in its use to detect and measure certain types of cellular activity, and in the study of the effects it produces when applied to growing plants. 

Bastenie and Zylberszac, in a general article on the former subject, point out that colchicine (1) brings into mitosis all cells which are in karyo-kinetic inuninence but which normally would slowly and successively reach mitosis, and (2) stops them at this stage. This has made possible a technique which picks out cell multiplication and can be used for detecting many types of hormonal stimulation, e.g., the action of follicular hormone and other oestrogens. ... 

There is a voluminous literature, chiefly of botanical interest, dealing with the effects of the application of colchicine to plants of economic importance such as tobacco, cotton,wheat and rice. ... 

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