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At least 73 records · Page 4Linked to original sources

PubMed1998

Stereochemical variations on the colchicine motif. Part 4. A remote metalation approach toward a colchicine analog with a five-membered B-ring.

Attempts to prepare a colchicine analog with a 5-membered B-ring by remote metalation of N,N-diethyl-3,4,5-trimethoxy-2-(5'-methoxy-4'-oxo-2', 5',7'-cycloheptatrienyl)-benzamide (2) led to ring contraction of the methoxytropone ring to the p-methoxycarbonylphenyl derivative (3). Dynamic 1H NMR investigations showed that the biaryl amide 2 exists as a mixture of diastereomers due to hindered rotation around both aryl-aryl and aryl-amide bonds, with rotational barriers of ca. 63 kJ mol-1. The colchicine and allocolchicine analogs 2 and 3 do not notably affect tubulin polymerization, despite the structural similarities with active analogs. The reduced tubulin binding activity of 2 and 3 may be a result of increasing steric bulk.

Colchicine↗

PubMed1997

Mechanism of tubulin-colchicine recognition: a kinetic study of the binding of the colchicine analogues colchicide and isocolchicine.

Colchicide (IDE) is a colchicine (COL) analogue in which the C-10 methoxy group is replaced by a hydrogen atom. Its binding to tubulin is accompanied by a quenching of the protein fluorescence. The fluorescence decrease shows a monoexponential time dependence. The observed rate constant increases in a non-linear way with the total concentration of IDE, allowing the determination of a binding constant for an initial binding site (K1=5300+/-300 M-1) and the rate constant for the subsequent isomerization (k2=0.071+/-0.002 s-1) at 25 degrees C. The rate constant, k-2, for the reversed isomerization can be determined by displacement experiments. Despite the minor alteration of the C-ring substituent, the kinetic and thermodynamic parameters of binding are substantially different from those of COL itself, for both steps. In isocolchicine (ISO) the carbonyl oxygen atom and the methoxy groups of the C-ring have been interchanged. Its binding to tubulin only results in small fluorescence and absorbance changes. Therefore competition experiments with MTC [2-methoxy-5-(2',3',4'-trimethoxyphenyl)-2,4, 6-cycloheptatrien-1-one] were performed. ISO competes rapidly and with low affinity with MTC. Fluorimetric titrations of tubulin with MDL (MDL 27048 or trans-1-(2,5 dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-propen-1 -one) in the presence and absence of ISO give evidence for the existence of a second, slow-reacting low-affinity site for ISO that is not accessible to MTC or MDL. The relevance of these results for the recognition of COL is analysed.

Animals↗

PubMed1978

Effect of colchicine on the antibody response. II. Demonstration of the inactivation of suppressor cell activities by colchicine.

The simultaneous administration of colchicine (CC) with a T-independent antigen, e.g. 2,4,6-trinitrophenyl-keyhold limpet hemocyanin-Sepharose, to intact animals effectively enhanced their hapten-specific plaque-forming cell (PFC) response. However, in congenitally athymic nude mice in which T-cell regulation was absent, CC was ineffective in producing enhancement. These observations suggest that the target cell acted upon by CC is most likely thymus-derived. Furthermore, the injection of CC with the co-polymer of L-glutamic acid50-L-tyrosine50 (GT) abolished GT-specific suppression of the PFC response to GT-methylated bovine serum albumin. Spleen cells from CC-treated and GT-primed hosts could no longer transfer suppressive activity to normal recipients. These results provide evidence that CC is capable of inactivating or eliminating suppressor cells or their precursors. Thus, CC-induced enhancement of the antibody response may be explained, at least in part, by its antimitotic, and hence lethal effect on dividing suppressor T cells.

Animals↗

PubMed1996

Evaluation of carbon-14-colchicine biodistribution with whole-body quantitative autoradiography in colchicine-sensitive and -resistant xenografts.

UNLABELLED: Quantitative autoradiography (QAR) with radiolabeled monoclonal antibodies in xenografted animals has been extensively described in the past, either on individual tissues or on the whole body. We applied whole-body QAR to identify multidrug resistant tumors using 14C-colchicine (14C-CHC). METHODS: Two groups of five animals each were xenografted with CHC-sensitive and CHC-resistant human neuroblastoma cells. Animals were injected intravenously with 4 microCi/0.11 mumole 14C-CHC per gram of body weight and sacrificed after 60 min. Whole-body QAR was carried out using 25-microns thick sections. RESULTS: Fusion images allowed direct comparison of 14C-CHC uptake in tumor and nontumor tissues. Mean 14C-CHC distribution in sensitive and resistant tumors was 882.0 +/- 43.6 and 399.6 +/- 157.7 nCi/g corresponding to 24.5 +/- 1.21 and 11.1 +/- 4.38 nmole/g, respectively (p < 0.001), with normal tissue distribution in both groups being similar. Three-dimensional QAR showed that the uptake of 14C-CHC was in the cellular zones of the tumor. This method has potential in biodistribution studies of novel radiopharmaceuticals such as 14C-CHC. CONCLUSION: These studies further suggest that PET imaging of 11C-CHC is feasible to distinguish between sensitive and resistant tumor deposits in vivo.

Animals↗

PubMed1951