Tubulin polymerisation

Tubulin is a major component of the cellular cytoskele-ton. Tubulin polymers (microtubules) are important for cell division (mitotic spindle) and the chemotaxis and phagocytosis of neutrophils. Prevention of tubulin polymerisation by colchicine accounts for the therapeutic effects of this drug in acute gouty arthritis and its anti-mitotic effects. 

Diazonamide A 46 (Scheme 6.4) is toxic to human colon HCT-116 cancer cells at 15 ng/mL. Other structures include cyclic peptides such as didemnin B 47 which has been discontinued in Phase II clinical trials, aplidin 48 which is currently in Phase II clinical studies for multiple myeloma and vitilevuamide 50 which effects tubulin polymerisation at micromolar concentrations. One of the... 

A number of drugs, which are known to bind with tubulin and inhibit its polymerisation to microtubules, have been evaluated in protozoal chemotherapy. The most notable are the alkaloids maytansine, ansamitocin P3, vinblastine and vin-cristin, which have been shown to be potent inhibitors of tubulin polymerisation in T. brucei. However, these are too toxic to be considered as useful trypanocidal agents [2]. 

SAR information about a series of 3-aminobenzophenone compounds (e.g. 6d and 6e), based on the mimic of the aminocombretastatin molecular skeleton, revealed that by the introduction of an amino group instead of a hydroxy group inhibition of tubulin polymerisation through binding to the colchicine binding site could fully be preserved or even improved [42]. 

Fig. 4 Tubulin polymerisation inhibitors possessing an indole moiety as a core structure...

Sulphonamides as E 7010 (17) inhibit tubulin polymerisation by binding to the colchicine site, exhibiting potent anti-proliferative activity in vitro (IC50 = 0,2 - 40ng/ml), currently investigated in clinical phase II studies [55,56] by Eisai/Abbott in patients with solid tumours. 

A364 -> T [116]. BMS-247550 has a potent tubulin polymerisation capacity (2,5 fold more potent as Taxol), a broad cytotoxicity (mean IC50 of 3.9 nM) and is efficacious in vivo after i.v. and p.o application [115]. A MTD with neutropenia as DLT (without G-CSF co-treatment) was determined and objective responses in breast and cervical cancer patients refractory to prior taxane therapy were observed [117]. In a clinical trial, the formation of microtubule bundles in peripheral blood mononuclear cells (PBMCs) was monitored and cell death occurred after peak microtubule bundle formation [118]. 

Interestingly, when the synthetically-derived allocolchicinoids ( )-19 and ( )-20 were subjected to the relevant binding assay they did not show inhibitory effects on tubulin polymerisation. Furthermore, they were not cytotoxic to L1210 (murine lymphocytic leukaemia) cells [34],... 

Long BH, Carboni JM, Wasserman AJ et al. Eleutherobin, a novel cytotoxic agent that induces tubulin polymerisation, is similar to paclitaxel (taxol). Cancer Res 1998 58 1111-1115. 

None of these compounds were inhibitors of tubulin polymerisation. This was obviously attributed to the presence of the bulky sugar on the double bond. Our developed methodology allowed the synthesis of the unknown simplified compounds 11. Even these compounds failed to inhibit tubulin polymerisation whereas some fluorinated analogues (F instead of CH2OH in 11) or ethoxy substituted ones (OEt instead of CH2OH in 11) did. Nevertheless some of compounds 10 were found to have antiproliferative properties in the submicromolar range against different cancer cell lines by a yet unknown mechanism. ... 

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