Tubulin inhibitory activity

The derivatives and analogues reported in the previous sections have been tested against a variety of biological activities tubulin inhibitory activity cytotoxicity antivascular and antitumor activities. 

Antilla and co-workers reported the enantioselective formation of N,N-aminals catalyzed 26 [99]. Recently, List s and Rueping s groups independently applied the methodology for the asymmetric synthesis of 2,3-dihydroquinazolinones, which exhibit potent tubulin inhibitory activities (Equation 10.52) [100]. 

Some of the earliest work in this area was reported by Blechert, who prepared the diastereomeric diols 13.1.1 416) and 13.1.2 417). Both compounds were reported as being able to inhibit the depolymerization of tubulin, but the level of this activity was not reported. An even more simplified set of analogs was prepared by Fuji and Kohno and their collaborators these investigators prepared the analogs 13.1.3-13.1.8, in which the alkyl chain comprised two to seven carbons 418) none of these compounds showed any promising tubulin inhibitory activity. 

Scheme 13 Representative Indoles with Tubulin Inhibitory Activity...

The sea hare Dolabella auricularia has been the source of the powerful cytotastic and antineoplastic constituents designated as dolastatins [311]. Some of these compounds are thiazole-containing cyclic peptides. They were found in very small quantities in the animal (ca. 1 mg each from 100 Kg), making the isolation and structural elucidation of these peptides exceptionally challenging. A review on the dolastatins, written by G. R. Pettit in 1997, covers the reported literature regarding their isolation, characterization, biological activity, and synthesis [312]. Pettit and coworkers reported the thiazole-containing dolastatins dolastatin 3 (404) [313], 10 (2) [314], and 18 (407) [315]. The most important dolastatin and the most potent antineoplastic and tubulin-inhibitory substance known to date is the unique linear pentapeptide dolastatin 10 (2). 

Cyclopropane analog " 98 showed microtubule disassembly inhibitory activity comparable with paclitaxel, but lower than docetaxel. The author thus demonstrated that the oxetane ring is not essential for the interaction of paclitaxel analogs with microtubules when the C-ring conformation is locked by cyclopropane, but the oxygen atom in the D ring of paclitaxel may participate in the stabilization of a dmg-tubulin complex. 

The projected Tubulin Polymerization Inhibitory activity is 85.9 CASE units ... 

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. 

Thiazole, triazole, tetrazole, pyrazole, imidazole analogues (the heteroaromatic ring replacing the stilbene core) were then prepared and tested for tubulin polymerization inhibitory activity using bovine brain tubulin cytotoxic activity against the colon 26 adenocarcinoma cancer cell line antitumor activity in the colon 26 murine tumor model. 

In the course of search for anticancer agents in the plant kingdom, Roux et al. [16] found that an EtOAc extract of the fruits of G. pyrifera exhibited significant inhibitory activity on the disassembly of microtubules into tubulin (63% inhibition at 6.67 pg mL 1). This activity did not correlate with a positive cytotoxicity in KB cells (12% inhibition at 10 pg mL 1). 

Although none of the pyrazolines have been tested as tubulin binders Jeong et al. reported the activity of pyrazolines for their lipid peroxidation inhibitory... 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

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