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PubMed2004

Total syntheses of colchicine in comparison: a journey through 50 years of synthetic organic chemistry.

Colchicine, the major alkaloid of the meadow saffron, is one of the most prominent natural products and, like other tubulin-binding natural products (e.g. taxol and the epothilones), exhibits great pharmaceutical potential. The first syntheses in the late 1950s were milestones in natural product synthesis. But even today this structurally supposedly simple molecule poses a challenge to synthetic chemists. Only in the last years have syntheses been developed that are efficient enough to provide novel structurally modified colchicine analogues. The comparative examination of all known colchicine total syntheses undertaken in this Review not only reveals the tremendous progress in synthetic organic methodology over the past decades, but also shows how the unique synthetic problems posed by this molecule can be solved in an exceptionally creative manner. Only a few target molecules have been synthesized in such multifaceted ways.

Chemistry, Organic↗
PubMed1981

An electron microscopic radioautographic study of collagen secretion in periodontal ligament fibroblasts of the mouse: II. Colchicine-treated fibroblasts.

Colchicine administered intravenously depolymerized microtubules and disrupted the normal organization of the Golgi apparatus in periodontal ligament fibroblasts. Radioautography with 3H-proline indicated that collagen secretion was completely inhibited during a period of approximately 4 hours following the onset of the colchicine effect. During this period of secretory inhibition, labeled collagen precursors were present within a variety of dense bodies, primarily located in a juxtanuclear location replacing the normal Golgi complex. The time course of 3H-proline labeling from 2 to 8 hours suggested that small, newly formed dense bodies fused to form larger dense bodies and pleomorphic structures (zebra bodies), within which collagen precursors appeared to undergo partial polymerization. Autophagosomes, many labeled with 3H-proline, also increased in number after colchicine administration. A gradual decline in 3H-proline label occurred from 4 to 24 hours, presumably due to exocytosis of dense bodies or by the digestion of labeled collagen precursors within autophagosomes. These results support the concept that an intact microtubular network is essential for the organized transport of collagen precursors, from the rough endoplasmic reticulum to the Golgi apparatus, and the eventual transport and exocytosis of collagen secretory granules.

Animals↗
PubMed1987

Reversible inhibition of microtubules and cell growth by the bicyclic colchicine analogue MTC.

2-methoxy-5-(2,3,4-trimethoxyphenyl) 2,4,6-cycloheptatrien-1-one (MTC) is a synthetic colchicine analogue, lacking the B ring of the alkaloid (Fitzgerald: Biochem. Pharmacol. 25:1381-1387, 1976). MTC has been shown to bind reversibly to the colchicine binding site of tubulin and to inhibit microtubule assembly in vitro (Andreu et al: Biochemistry 23:1742-1752, 1984; Bane et al: J. Biol. Chem. 259:7391-7398, 1984). Its action on different cultured cell lines (PtK2, Pk15, and SV-3T3) has now been studied. 0.2 X 10(-6) M MTC stopped Pk15 and SV-3T3 cell growth, inducing an accumulation of mitoses in a few hours. Removal of MTC from the culture medium rapidly restored normal mitotic index and growth rates. Partial depolymerization of the cytoplasmic microtubules of PtK2 cells was observed at concentrations ranging from 2 to 5 X 10(-7) M. Maximal microtubule network depolymerization was obtained after 4 h of treatment with 2 to 5 X 10(-6) M MTC or at a higher MTC concentration (2 X 10(-5) M) for less than 2 h. Removal of 2 X 10(-5) M MTC (the highest MTC concentration used) from the culture medium resulted in almost complete microtubule polymerization after 10 min of drug recovery and a normal microtubule network in 20-30 min. MTC constitutes an antimitotic drug directed to the colchicine site. It is water-soluble, shows a fast and reversible action, and may therefore be employed as a convenient tool to study cellular microtubule-dependent functions.

Animals↗
PubMed1992

Differential sorting of beta tubulin isotypes into colchicine-stable microtubules during neuronal and muscle differentiation of embryonal carcinoma cells.

Pluripotent P19 embryonal carcinoma (EC) cells were differentiated along the neuronal and muscle pathways. Comparisons of class I, II, III, and IV beta tubulin isotypes in total and colchicine-stable microtubule (MT) arrays from uncommitted EC, neuronal, and muscle cells were made by immunoblotting and by indirect immunofluorescence microscopy. In undifferentiated EC cells the relative amounts of these four isotypes are the same in both the total and stable MT populations. Subcellular sorting of beta tubulin isotypes was demonstrated in both neuronal and muscle differentiated cells. During neuronal differentiation, class II beta tubulin is preferentially incorporated into the colchicine-stable MTs while class III beta tubulin is preferentially found in the colchicine-labile MTs. The subcellular sorting of class II into stable MTs correlates with the increased staining of MAP 1B, and with the expression of MAP 2C and tau. Although muscle differentiated cells express class II beta tubulin, stable MTs in these cells do not preferentially incorporate this isotype but instead show increased incorporation of class IV beta tubulin. Muscle cells do not show high levels of MAP 1B and do not express MAP 2C or tau. These results are consistent with the hypothesis that a subcellular sorting of tubulin isotypes is the result of a complex interaction between tubulin isotypes and MT-associated proteins.

Animals↗
PubMed1993

Colchicine-induced stimulation of PMN motility related to cytoskeletal changes in actin, alpha-actinin, and myosin.

Colchicine-induced stimulation of polymorphonuclear leukocyte (PMN) locomotion is an interesting model because extension of blebs at the front occurs at a rate (about 2.4 microns/s) which is far above that reported for growth of actin filaments. The following cytoskeletal changes were observed in colchicine-treated PMNs: (1) a small increase in cytoskeleton-associated actin was noted, as well as a somewhat more pronounced increase in cytoskeleton-associated alpha-actinin, as compared with untreated or DMSO-treated controls. There was, however, no measurable increase in F-actin as determined by NBD-phallacidin binding; (2) the values for the ratio (alpha-actinin/actin) are lower in PMNs treated with colchicine for 30 min, as compared with PMNs stimulated with fNLPNTL for 1 minute (non-polar ruffling cells) or 30 min (polarized locomoting cells); thus, this ratio may depend on the type of PMN motility; (3) in polarized PMNs F-actin was mainly located linearly all along the cell membrane; there was more intense staining at the front of the cells; (4) alpha-actinin appeared to colocalize with F-actin at the leading front, but not with F-actin at the tail of polarized cells; (5) myosin was preferentially found at the rear part of polarized cells but not or only to a small extent at the front. Our data indicate a close functional correlation between microtubules and microfilaments. We speculate that F-actin in combination with alpha-actinin promotes expansion of pseudopods, whereas myosin combined with F-actin promotes contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Actinin↗
PubMed1988

Distributions of pro-vasopressin expressing and pro-vasopressin deficient CRH neurons in the paraventricular hypothalamic nucleus of colchicine-treated normal and adrenalectomized rats.

The corticotropin-releasing hormone (CRH) neurosecretory system in normal rats consists of two major subpopulations of parvicellular neurons in the hypothalamic paraventricular nucleus distinguished by the presence or absence of coexistent vasopressin precursor (pro-AVP)-derived peptides. These neurons project to the external zone of the median eminence, where the two subtypes of axons (CRH +/AVP + and CRH+/AVP-) were previously found to be approximately equal in number. The present study was undertaken 1) to determine whether the relative numbers of pro-AVP expressing and pro-AVP deficient perikarya in the paraventricular nucleus corresponded to what we previously found for the axons in the median eminence, 2) to map the two cell types throughout the entire paraventricular nucleus to determine whether significant differences existed in their distributions, and 3) to ascertain whether or not the pro-AVP deficient subpopulation expressed pro-AVP after adrenalectomy. Postembedding electron microscopic immunocytochemistry on serial ultrathin sections was used to identify the peptide phenotypes of perikarya in the paraventricular nucleus in normal rats and 7 days after adrenalectomy with and without colchicine treatment. The peptide phenotypes of neuronal perikarya in the paraventricular nucleus were identified by using antibodies to CRH, AVP, neurophysin (NP), the C-terminal glycopeptide of pro-AVP (GP), and oxytocin-associated neurophysin (NPOT). Groups of three serial coronal ultrathin sections were analyzed at 200-micron intervals throughout the entire rostrocaudal extent of the paraventricular nucleus. The sections in each group were stained for CRH, a pro-AVP-derived peptide (AVP, NP, or GP), and NPOT, respectively. Parvicellular CRH neurons were defined as CRH-positive cells, approximately 10 micron in diameter, that did not contain detectable NPOT. Pro-AVP expressing cells were defined as staining positively for AVP, GP, or NP and negatively for NPOT. Approximately equal numbers of pro-AVP expressing ("NPAVP+") and pro-AVP deficient ("NPAVP-") parvicellular CRH neurons were found within the paraventricular nucleus of colchicine-treated normal rats, and the two subtypes were distributed differently within the paraventricular nucleus. Although the pro-AVP expressing CRH cells stained intensely for NP and GP, staining for AVP was quite variable and difficult to quantify in colchicine-treated normal animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenalectomy↗
PubMed1991

Similarities in the ultrastructural distribution of nerve growth factor receptor-like immunoreactivity in cerebellar Purkinje cells of the neonatal and colchicine-treated adult rat.

The intracellular distribution of nerve growth factor receptor immunoreactivity was examined by electron microscopy in the cerebellum of adult and postnatal day 12 rats. The very faint immunostaining in Purkinje cells of naive adult animals was greatly amplified after colchicine treatment. Neonatal cerebellum, in contrast, contained prominent immunoreactivity in both Purkinje cells and germinal cells of the external granular layer. Intracellular distribution of the nerve growth factor receptor reaction product was very similar in Purkinje cells of both neonatal and colchicine-treated adult animals. It was consistently present along the perikaryal cell membrane, in segments of the rough endoplasmic reticulum and Golgi complex. Numerous membrane-bound aggregates of immunoreactive vesicles resembling multivesicular bodies (secondary lysosomes) were scattered throughout the cell soma, although less frequently in neonatal rats. Bulbous expansions along the proximal axons of colchicine-treated Purkinje cells were filled with such immunoreactive multivesicular bodies. These cells also displayed evidence of nerve growth factor receptor internalization in the form of immunoreactive coated vesicles situated near the cell membrane. In addition to the staining in Purkinje cells, neonatal cerebellum contained high amounts of nerve growth factor receptor reaction product along the cell membrane of germinal cells in the external granular layer. Although Purkinje cells of naive adult animals possessed little or no cell membrane-related nerve growth factor receptor immunoreactivity, reaction product was sometimes seen in cisternae of the rough endoplasmic reticulum and Golgi apparatus. These findings provide electron microscopic immunocytochemical evidence of nerve growth factor receptor synthesis, internalization, and catabolism in noncholinergic neurons of the central nervous system.

Aging↗
PubMed1995

Expression of FGF-2 and FGF receptor type 1 in the adult rat brainstem: effect of colchicine.

In the adult rat brainstem, neuronal subpopulations of several motor and sensory nuclei display basic fibroblast growth factor (bFGF or FGF-2) immunoreactivity (IR; Grothe et al. J. Comp. Neurol. 305:328-336). In the present study we demonstrate that FGF-2-IR correlates with staining for the high-affinity FGF-receptor 1. Intracerebroventricular injection of colchicine leads to the disappearance or substantial reduction of FGF-2-IR in the hypoglossal, facial, trigeminal motor, trochlear, and mesencephalic trigeminal nuclei. In contrast, FGF-2-IR appears in many perikarya of the red nucleus and the medial nucleus of the trapezoid body, whereas in control rats both nuclei showed immunostained fibers and almost no immunoreactive cell bodies. This dramatic change of FGF-2-IR could be explained by the ability of colchicine to block fast axonal transport. Cranial nuclei may internalize FGF-2 at the periphery via high-affinity receptors and retrogradely transport the molecule to their perikarya. The red nucleus and the medial nucleus of the trapezoid body may synthesize FGF-2 and provide the growth factor to afferent or efferent neurons. The presence of FGF-2 mRNA in brainstem extract and the absence of the FGF-2 transcript in extracts of the hypoglossal nucleus corroborate this suggestion. The effect of colchicine on FGF-2-IR in the brainstem nuclei suggests that FGF-2 could be specifically retrogradely transported in other cranial nuclei, in addition to the hypoglossal system. Together with the ability of FGF-2 to stimulate neuronal survival, this result strongly supports the hypothesis that FGF-2 is acting as a neurotrophic factor on specific central neuron populations.

Animals↗
PubMedDate not supplied

Effect of colchicine and phalloidin on the distribution of three plasma membrane antigens in rat hepatocytes: comparison with bile duct ligation.

The hepatocyte plasma membrane presents a morphological and functional regionalization into three domains: the sinusoidal; the lateral, and the canalicular. The mechanisms responsible for the biogenesis and maintenance of this regionalization are poorly understood. In this work, we have used colchicine and phalloidin, two drugs known to interfere with the secretory processes in hepatocytes, to study whether they also affect the transport of membrane proteins. The localization of three plasma membrane antigens was studied by light and electron microscopy using monoclonal antibodies identifying either the sinusoidal (A39) or the lateral (B1) or the canalicular (B10) domains in normal hepatocytes. In rats injected with colchicine (0.25 mg per 100 gm), A39 moved from the sinusoidal membrane to the lateral and canalicular ones, whereas B10 was displaced from the canalicular to the sinusoidal and lateral membranes, resulting after 8 hr in an almost equal labeling of the three domains with both antibodies. In rats injected daily for 7 days with phalloidin (50 micrograms per 100 gm), A 39 became mainly localized on the bile canalicular membrane instead of the sinusoidal one; B10 predominated on the canalicular membrane as in controls but in places it labeled the sinusoidal and lateral domains as well. In bile duct-ligated rats studied for comparison for 4, 10 or 21 days, A39 and B10 localizations evolved as after phalloidin, but the changes were more marked. B1 was not affected by any of the treatments. In conclusion, colchicine, phalloidin and bile duct ligation do not seem to hinder the antigens in reaching the plasma membrane, but induce a redistribution of two of them, suggesting a disturbance in the biogenesis and/or control of the plasma membrane regionalization. Such an abnormal distribution could be involved in--or contribute to--the initiation of cholestasis.

Animals↗
PubMed1977

Microtubules in the "chloride cell" of the gill and disruptive effects of colchicine on the salt balance of the sea water adapted Mugil capito.

Electron-microscopic examination of the gill of the grey mullet, Mugil capito adapted to sea water, reveals the presence of numerous microtubules in the apical region of the mitochondria-rich cells. No microtubules are found in other types of epithelial cell. Exposure of the fish to colchicine (10(-4)M) for four hours induces a 20% increase of plasma Na and Cl. Colchicine leaves the water permeability of the gill unchanged but Cl and Na exchange fluxes are inhibited by 30-50% and the gill potential pattern is altered. Salt gain replaces salt excretion across the gill. The K dependent Na and Cl efflux components, independent of the gill potential shift produced by K, are totally inhibited by colchicine. Exposure to lumicolchicine is not followed by a significant change of these Na and Cl efflux-components and potential pattern. The possibility that microtubules intervene in the salt excretion process across the chloride cells is discussed.

Adaptation, Physiological↗
PubMed1980

Differential pulse polarographic determination of colchicine.

A differential pulse polarographic method for the analysis of colchicine-containing dosage forms is described. The reduction of the tropolone carbonyl is useful for quantitative analysis in that the relationship of the colchicine concentration to the current is linear over the concentration range of 0 to approximately 50 micrograms/ml, with a slight negative deviation at higher concentration. The procedure involves no preliminary treatment, is simple and specific, and is applicable to the assay of composite tablets, individual tablets, and injectable solutions. Polarography is conduction on a solution of colchicine in pH 1.81 Britton-Robinson buffer with 0.01% alkylphenoxy polyethoxyethanol. The quantitative analysis is achieved using the method of standard addition. A relative standard deviation of 3.2% was obtained for tablets. The results agree with those obtained using the USP XIX method.

Colchicine↗
PubMed1989

Effect of treatment with phospholipase A2, colchicine, and beta-galactosidase on agglutination of rat hepatocytes.

The effects of phospholipase A2, colchicine, and beta-galactosidase on concanavalin A-induced agglutination of viable hepatocytes isolated from normal and diabetic rats are reported. Phospholipase A2 (0.92 microgram/mL), colchicine (400 micrograms/mL), and beta-galactosidase (300 micrograms/mL) treatments caused a significant increase in the agglutination rate of hepatocytes. These findings suggest that phospholipase A2 treatment resulted in the unshielding of lectin receptors. Colchicine treatment seemed to release those receptors from cellular restraints which tend to separate and/or direct them. The promoting effect of beta-galactosidase could be attributed to a decrease in repulsive forces due to a reduction in net negative charge density after removal of N-acetylneuraminic acid residues. Normal rat hepatocytes seem to be richer in galactosides, phospholipids, and the microfilament-microtubule network than their diabetic counterparts.

Agglutination↗
PubMed1990

System approach to the transepithelial transport across rat jejunal enterocytes: effect of cytochalasin B, colchicine, and ethylenediaminetetraacetic acid on butyric acid transport.

A three-compartment physical model is devised for transepithelial passive transport across intestinal cells. The mathematical equations derived from the model allow the simultaneous and quantitative measurements, in the form of permeability coefficients, of solute transport across both the luminal-serosal and serosal-blood barriers. The proposed model is used to study the involvement of the cytoskeleton in butyric acid absorption by the rat jejunum. Alterations in cytoskeletal functions are introduced by the administration of microfilamentous and microtubular altering agents such as cytochalasin, colchicine, or EDTA. An isolated jejunal segment perfused with a buffer containing labeled butyric acid was homogenized at the end of the experiment and assayed for its butyric acid content. During the perfusion, portal blood samples, as well as perfusate samples collected 10 cm distal to the perfusion site were drawn at 5-min intervals and assayed for their radioactivity. Cytochalasin was found to decrease the permeability of the mucosal membrane to butyric acid and to increase that of the serosal membrane. Colchicine did not have any effect either on the mucosal or on the serosal side. Cytochalasin and colchicine, when given in the same experiment, increased the permeability of the serosal membrane to butyric acid, but were without any effect on the mucosal barrier. Also, EDTA had no effect on the mucosal side, but decreased significantly the permeability of the serosal membrane to the fatty acid.

Animals↗
PubMed1992

Effects of cytochalasin, colchicine, and ethylenediaminetetraacetic acid on linoleic acid transport across rat jejunal enterocytes.

The involvement and the site of interference of the cytoskeleton in the transport of linoleic acid across the rat jejunum was investigated by administration of microfilamentous and microtubular altering agents such as cytochalasin, colchicine, and ethylenediaminetetraacetic acid (EDTA). An isolated jejunal segment was perfused with a buffer containing labeled linoleic acid, and portal blood and perfusate samples were collected concomitantly at 5-min intervals and assayed for their radioactivity. At the end of the perfusion, the amount of radioactivity retained in the intestine was also determined. The results were analyzed by using a three-compartment physical model that allows the determination of mucosal and serosal permeability coefficients, from which changes in the permeability of the mucosal and serosal membranes were assessed. Cytochalasin decreased the permeability of the mucosal membrane to linoleic acid, but not that of the serosal membrane. The administration of colchicine, EDTA, or cytochalasin + colchicine increased the permeability of the serosal membrane but did not affect the mucosal membrane.

Animals↗
PubMed2004

Cytoskeletal myotoxicity from simvastatin and colchicine.

We report the case of a 79-year-old man with mild chronic renal failure who developed severe rhabdomyolysis after combined exposure to simvastatin and colchicine. Colchicine induces myopathy through disruption of microtubular function with subsequent vacuolization and pseudomyelinic body accumulation. Statin therapy is associated with myonecrosis, membranous myeloid bodies, and vacuolization, presumably as a function of impaired isoprenoid metabolism. Vesicle trafficking requires small G-protein prenylation and statins can disrupt cytoskeletal integrity. We propose that synergistic cytoskeletal myotoxicity may account for the extreme elevation of serum creatine kinase not previously reported in pure colchicine myopathy.

Aged↗
PubMed1989

Electrodiagnosis of human colchicine myoneuropathy.

Colchicine may produce a neuromuscular disorder even when given in customary doses. We report the electrodiagnostic features in eight pathologically proven cases of colchicine-induced myoneuropathy. Myopathic motor unit potentials and early recruitment were found in proximal limb and truncal muscles, frequently with fibrillations, positive sharp waves, or complex repetitive discharges. These electromyographic findings correlated with the course of the weakness, which rapidly resolved within weeks of drug discontinuation, indicating that the major functional disturbance in the patients was myopathy. The accompanying signs of axonal neuropathy persisted longer, with little functional consequence. Although often misrecognized as polymyositis, colchicine myoneuropathy was identifiable by the rapid clinical and electrophysiologic improvement following drug withdrawal as well as by its distinctive morphology.

Aged↗
PubMed1999

Biosynthesis of radiolabeled curacin A and its rapid and apparently irreversible binding to the colchicine site of tubulin.

Curacin A is a potent competitive inhibitor of colchicine binding to tubulin, and it inhibits the growth of tumor cells. We prepared [(14)C]curacin A biosynthetically to investigate its interaction with tubulin. Binding was rapid, even at 0 degrees C, with a minimum k(f) of 4.4 x 10(3) M(-1) s(-1). We were unable to demonstrate any dissociation of the [(14)C]curacin A from tubulin. Consistent with these observations, the K(a) value was so high that an accurate determination by Scatchard analysis was not possible. The [(14)C]curacin A was released from tubulin following urea treatment, indicating that covalent bond formation does not occur. We concluded that curacin A binds more tightly to tubulin than does colchicine. Besides high-affinity binding to the colchicine site, we observed significant superstoichiometric amounts of the [(14)C]curacin A bound to tubulin, and Scatchard analysis confirmed the presence of two binding sites of relatively low affinity with a K(a) of 3.2 x 10(-5) M(-1).

Antineoplastic Agents↗
PubMed1994

Induction of apoptotic cell death in differentiating neuroblastoma SH-SY5Y cells by colchicine.

In retinoic acid (RA)-differentiated SH-SY5Y cell cultures, colchicine could induce cell death, accompanied by the typical ladder pattern of DNA fragmentation found in apoptotic cells. This effect could be attenuated by the protein synthesis inhibitor cycloheximide. The protein kinase inhibitor H-89 efficiently reduced colchicine-induced cell death. These results suggest that the mechanism for colchicine-induced cell death may act, at least in part, through the activation of apoptosis in differentiating SH-SY5Y cells.

Apoptosis↗