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Kombretastatyna A-4 (CA-4) i jej analogi : synteza i aktywność biologiczna

Dzierzbicka K., Kubacka P., Renusz S., Kołodziejczyk A.M.

Wiadomości Chemiczne

2008

[Z] 62, 11-12

1037-1064

This article described synthesis and biological activity of combretastatin A-4 (CA-4) and its analogues. Combretastatin A-4 (CA-4), a natural product isolated from the South African bush willow tree Combretum caffrum, binds to the colchicine binding site and inhibits the polymerization of microtubules. CA-4 exhibits potent cytotoxicity against a variety of human cancer cell lines including multidrug-resistant (MDR) cell lines [5-7]. The studies of structure-activity relationship (SAR) of CA-4 1 (Fig. 1) showed that 3,4,5-trimethoxy substitution on the A ring and the 4'-methoxy group on the B ring and the cis-olefin configuration are crucial for potent cytotoxicity, while the 3'-hydroxy group is optional [5-7]. A many of CA-4 analogues were synthesized where the double bond have been replaced by introduction of nonheterocyclic groups (e.g. ethers, olefins, ketones, sulfonates, sulfonamides, amide derivatives, amine, cyclopentanes) or heterocyclic groups containing five-membered rings (e.g. pyrazoles, thiazoles, triazoles, tetrazoles, oxazoles, furans, dioxolanes, thiophenes) and indoles [5, 7, 41, 56] (Fig. 9-12). Up to now, many CA-4 analogues and their biological activity have been extensively studied and three derivatives are currently in clinical trials: a water-soluble disodium phosphate derivative of CA-4 (CA-4P) 11c (Fig. 3); Oxi-4503, a water-soluble combretastatin A-1 (CA-1diP) 4a (Fig. 1); and AC7700 59e (Scheme 7) an aminocombretastatin prodrug developed in Japan in 1998 [5-10, 34].

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.