Microtubule inhibitor

Makarov AA, Tsvetkov PO, Villard C, Esquieu D, Pourroy B, Fahy J, Braguer D, Peyrot V, Lafitte D. (2007) Vinflunine, a novel microtubule inhibitor, suppresses calmodulin interaction with the microtubule-associated protein STOP. Biochemistry 46 14899-14906. 

Altmann KH, Wartmann M, O Reilly T. Epothilones and related structures—anew class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000 1470(3) M79-91. 

Kasai T, Iwanaga Y, Iha H et al. Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. JBiol Chem 2002 277 5187-5193. 

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to 6-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy. 

Stitt, A.W and Fairweather, I. (1992) Spermatogenesis in Fasciola hepatica an ultrastructrual comparison of the effects of the anthelmintic, triclabendazole ( Fasinex ) and the microtubule inhibitor, tubulozole. Invertebrate Reproduction and Development 22, 139-150. 

THE CHEMISTRY AND BIOLOGY OF EPOTHILONES—LEAD STRUCTURES FOR THE DISCOVERY OF IMPROVED MICROTUBULE INHIBITORS... 

As indicated above, the first compound of the epothilone class of microtubule inhibitors to enter clinical trials was Epo B EPO906, Novartis vide supra). This involved initial testing in two phase I studies, employing either a weekly or a... 

Beckers T, Mahboobi S. Natural, semisynfiietic and synfiietic microtubule inhibitors for cancer fiierapy. Drugs Future 2003 28 767-785. 

Meyvisch, C., Storme, G., Bruyneel, E. and Mareel, M. (1983). Invasiveness and tumorigenicity of MO4 mouse fibrosarcoma cells pretreated with microtubule inhibitors. Clin. Exp. Metabol. 1, 17-28. 

A microtubule inhibitor, rhizoxin (Fig. 1) was found in the culture filtrate of Rhizopus chinensis (j>). Subsequently, Iwasaki et al. (7 ) determined the chemical structure of this compound, and the antitubulin activity of rhizoxin was characterized using porcine brain tubulin (j3). 

Khan, S. H., 8c Wahl, G. M. (1998). p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Research, 58, 396—401. 

However, in 1942 it was removed from U. S. pharmacopeia because of its severe gastrointestinal toxicity. Currently, it still remains as an effective therapy for treatment of venereal warts [25]. Furthermore, podophyllotoxin and its derivatives have been extensively studied in the last 60 years for their powerful antitumor effects. Podophyllotoxin itself is a powerful microtubule inhibitor. Microtubules are tubular polymers whose protomeric unit (a and 3-tubulin) forms an heterodimer and are the dynamic constituents of the cytoskeleton. The cytoplasm of eukaryotic cells contains a soluble pool of unpolymerised tubulin protomers as well as an organised array of microtubules. Microtubules can be rapidly assembled or disassembled in response to various stimuli with little or no change in the total amount of tubuline. Cytoplasmatic microtubules are... 

L.W. Ma, K. Berg, H.E. Danielsen, O. Kaalhus, V. lani, J. Moan (1996). Enhanced antitumor effect of photodynamic therapy by microtubule inhibitors. Cancer Lett., 109, 129-139. 

Callahan HL, Kelley C, Pereira T et al. Microtubule inhibitors Structure-activity analyses suggest rational models to identify potentially active compounds. Antimicrob Agents Chemother 1996 40 947-952. 

Wienecke A, Bacher G. Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin. Cancer Res 2009 69(l) 171-7. 

Taxol is a diterpene alkaloid isolated as an anticancer agent from the bark of T. brevifolia [1]. Subsequently, it was reported that this alkaloid possessed clinical effects for the treatment of leukemia and had excellent efects on refractory ovarian and mammary cancer. The mechanism of action of this alkaloid is to promote the formation of microtubules, the opposite action to that of the microtubule inhibitors hke podophyllotoxin, colchicine, and vinblastine [2,3]. 

Recently, Sun utilized this chemistry for a straightforward and highly efHcient assembly of the indolizine core 324 in the synthesis of a microtubule inhibitor STA-5312 325, possessing potent antitumor activity against multidrug-resistant-type cancers (Scheme 9.112) [295]. 

Perez EA. Microtubule inhibitors differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther 2009 8(8) 2086-95. 

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