Inhibitor tubulin

ABI-007 (Abraxane) Albumin-coated nanoparticle paclitaxel tubulin inhibitor Breast cancer Randomized Phase II trial... 

Newman S. (2007) Eribulin, a simplified ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Curr Opin Invest Drugs 8 1057-1066. 

Colchicine site ligands are structurally simpler than taxol or vinblastine site compounds the extent of the colchicine site is also smaller. This is confirmed with the observation that podophyllotoxin interacts with the same P tubulin residues as colchicine [15]. Modehng studies also suggest a pocket of restricted size for other colchicine site ligands [40] while some extensions of the site have been postulated in an approach combining modeling and virtual screening [61]. Biochemical evaluations have confirmed some of the hits as new tubulin inhibitors but no structural data are available yet that confirm whether they actually make use of an additional cavity near the colchicine site. 

Biophores of some tubulin inhibitors were identified by CASE on molecules such as colchicine, podophyllotoxin, and dihydrocombrestatin (see Combes, 2000). These chemicals might act as nongenotoxic carcinogens by being able to bind to tubulin, inducing phenomena such as aneuploidy. 

Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989 45 209-211. 

Dorr RT, Dvorakova K, Snead K, Alberts DS, Salmon SE, Pettit GR. Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor. Invest. New Drugs 1996 14 131-137. 

Semisynthesis and degradation of the tubulin inhibitors epothilone (macrocyclic ketolactone) and tubulysin (thiazole derivative) 03PAC167. 

DEVELOPMENT OF TUBULIN INHIBITORS AS ANTIMITOTIC AGENTS FOR CANCER THERAPY... 

Tubulin binding agents interfere with the dynamic instability of microtubules and thereby arrest mitotic cells in the M-phase of the cell division cycle, finally leading to induction of apoptosis. Most, if not all, tubulin inhibitors bind within fl-tubulin to distinct epitopes. They are... 

THE FAMILY OF COLCHICINE-SITE BINDING TUBULIN INHIBITORS... 

A second group of tubulin inhibitors is represented by compounds exhibiting the combretastatin structure. Combretastatin (5) itself, as well as combretastatins A-l (5a), A-4 (5b) and A-2 (5d), have first been extracted from a South African tree Combretum caffrum by Pettit et al., depicting affinity to the colchicine binding site [28], Syntheses of various analogues of this simple molecule, thereafter, have been reported [16,29, 30] (see also Scheme 1). 

Diarylindoles, e.g. (7), classified as heterocombretastatins with respect to the ethylene bridged diaryl structure and the 3,4,5-trimethoxy substitution pattern, displayed cytotoxicity especially towards leukaemia, non-small cell lung and CNS cancers [33, 43]. A modification of the tubulin inhibitor (8) [44] led to the thiophene and indole analogue (9) with remaining high cytotoxicity (ICso-values in the range of 10 to 100 nM) [45]. The structure of (9) also represents a fragment of the tetracyclic tubulin inhibitor (10) [46] that showed similar activity. 

Fig. 6 Structures of antimitotic sulphonamides. Dependent on the pharmacophore core structure the respective compounds can be classified as reversible (17) or irreversible (18) tubulin inhibitors respectively as cell cycle inhibitor (19).

Havens CG, Bryant N, Asher L et d. Cellular effects of leishmanial tubulin inhibitors on Leishma-nia donovani. Mol Biochem Parasitol 2000 110 223-36. 

Leishmania, this compound does not appear to act through a tubulin mechanism in live parasites. This was conduded from the observation that incubation of WR85915 (21) with L. donovani did not cause the usual cell types observed with other tubulin inhibitors and the parasites did not accumulate in G2M phase. WR85915 (21) must therefore be acting on other cellular tai et(s) besides or in addition to tubulin. 

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