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Inhibitory mikrotubul w terapii przeciwnowotworowej

Dzierzbicka K., Kołodziejczyk A.M.

Wiadomości Chemiczne

2006

[Z] 60, 5-6

345-364

Microtubule targeting drugs being in the late preclinical or early clinical development are described in this article. New semisynthetic paclitaxel analogues, natural compounds of diverse structure such as epothilones, combretastatins, colchino-ids or dolastatins and synthetic compounds of low molecular weight such as heterocombretastatins, sulfonamides, phenstatins, indoles and quinolones belong to this category of anticancer medicines. Microtubules are hollow tubes consisting of L- and B-tubulin heterodimer proteins that polymerize parallelly to a cylindrical axis. The targeting of microtubules is an important mechanism in cancer chemotherapy for such drugs as the vinca alkaloids (vincristine (1), vin-blastine (la)), podophilotoxin, their semisynthetic analogues and taxanes (paclitaxel (2), docetaxel (3)) known of their great usefulness in the anticancer therapy. These agents may stabilize microtubules, as the taxanes do, or destabilize them, as it is in the case of the vinca alkaloids. Today, more than 30 compounds targeting tubulin, either stabilizing or destabilizing microtubule dynamics, are in late preclinical or early clinical development. Despite of more than 30 years after the discovery of paclitaxel microtubule inhibitors they are still of the topic of interest of all over the world. In the end of 1990 and up to 2005 year survey articles on the microtubule inhibitors were published .We expect now that the paper which presents last results study may be useful.

Ekstaza i udręka, czyli o chemii taksolu

Kacprzak K.

Wiadomości Chemiczne

1998

[Z] 52, 11-12

843--870

Taxol (1), highly functionalised complex diterpenoid originally derived from the bark of Pacific yew, has received in recent decade wide attention of scientists in all fields of life sciences and chemistry, after the discovery of its strong and unique anticancer properties. Fast and spectracular career of this molecule is a subject of the present review. The Jarge scale of research on taxol is the consequence of public and commercial response to successful treatment of various cancer diseases and impossibility of solving basic technological and intellectual problems such as: production, drug formulation, structure-activity relationship elucidation. The discussion is divided into following sections: 1. Activity and pharmacological phenomena of taxol. 2. Production of taxol by biotechnological and chemical methods, including synthesis of taxol side chain. 3. Structure-activity relationship (SAR) of taxoids. After Horwitz reported in 1979 a strongly antimitotic activity of taxol, interest in developing the pharmacology and biochemistry of this class of natural products increased. Taxol molecule promotes anticancer activity by enhancing polymerization of tubulin and stabilization of microtubules. This process has the effect of inhibiting the normal dynamic reorganization of the cytoskeleton (with consists of microtubules) that is necessary for interphase and cell division in mitosis. Taxol and taxotere are successfully used for the treatment of a variety of cancers, in particular ovarian and breast cancer. The biggest problem hindering wider application of this drug is its limited availability from natural sources. One kg of Taxus brevifolia bark yields only 100-170 mg of taxol, after long and complicated extraction procedure. Since the yew is slow growing species this method of obtaining the drug is controvertible and unprofitable. An alternative source of taxol is semisynthesis, where natural precursor of taxol 10-deacetylbaccatin (10-DAB) can be extracted from regenerable twigs of popular yew Taxus baccata and after coupling with synthetically prepared side chain can be converted to taxol or taxotere. Taxol has also been prepared by a number of total syntheses but none of these is expected to enter the phase of commercial production. Biotechnological approaches to production by tissue culture or fungi cultivation have been reprted. Studies in the area of taxoids structure-activity relationships have first demonstrated two basic principles. The so-called 'southern' substituents, such as C-2 benzoate and the side chain, are crucial for the activity. 'Northern' substituents at C-7, C-9 and C-10 can be changed without drastic effect on the activity. The role of the substituents at C-1, the oxetane ring and diterpenoid core modifications are less well understood. There are many reports of significant activity of highly transformed taxoids, including those with: modified ABC core, open C-ring structure and aromatic C-ring. These results indicate the possibility of obtaining a synthetic, structurally simplified variant of taxol.