Combretastatin cell lines

B, Aboukameel A, Pettit GR, Al-Katib AM. Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation 87. and polyADP-ribose polymerase cleavage. Clin. Cancer Res. 2002 8 2735-2741. 

Among the modifications of ring A, fluorcombstatin and related 3-halostilbenes have been recently reported [7, 14]. The fluoro, chloro, and bromo halocombstatins were nearly equivalent to Combretastatin A-4 as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin and retained the powerful human cancer cell line inhibitory activity of combretastatin A-4. 

For example, starting from the synthetic ( )-isomer of natural combretastatin A-4 chiral hydroxylation (Sharpless) reactions produced the R,R) and (5, 5, )-diols (56 and 57, Scheme 14) which were evaluated against a series of cancer cell lines, and tubulin [35]. The dihydroxylation protocol was applied also to Combretastatin A-4 [17]. 

A series of arylbenzyl ethers and arylbenzylamines based on combretastatin A-4 was prepared and evaluated for anticancer activity against the K562 human chronic myelogenous leukaemia cell line [39]. Among them, the two benzyl ethers 62 and 64, which have the two aryl groups separated by two atoms, thereby mimicking more closely the arrangement present in Combretastatin A-4 were prepared (Schemes 15 and 16). 

The potency of the 3 -amino-4 -dimethylamino analogue against a panel of tumor cell lines (P-388, A-549, HT-29, MEL-28 or HeLa, HI 16, H-60) is even higher than that of Combretastatin A-4 or the related 3 -amino analogue. It is remarkable that this derivative, which is the most cytotoxic, has no effect on tubulin polymerization at concentrations below 30 )iM. This fact is in contrast to the usual behaviour of other combretastatin analogues, which always display a strong inhibitory effect on tubulin polymerization whenever they are cytotoxic in the submicromolar range. 

The Gewald aminothiophene synthesis was employed in the generation of 2-amino-3-(3,4,5-trimethoxybenzoyl)-5-aryl thiophenes as derivatives of the anti-tubulin agent combretastatin A." Condensation of 2,5-dihydroxy-1,4-dithiane with 3-oxo-3-(3,4,5-trimethoxyphenyl)-propionitrile and elemental sulfur in the presence of triethylamine afforded the thiophene product in 74% yield. Further synthetic steps yielded an antitubulin agent that not only inhibited tubulin polymerization but also showed anti-proliferation activity against both L1210 and K562 cancer cell lines. 

A new series of aryl-substituted imidazol-2-one derivatives structurally related to combretastatin A-4 were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line 65]. The highly active compounds also exhibited inhibitory activity against tumor growth... 

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