Tubulin stabilization

Epothilone D (195) -do- 9,10-Didehydro-epothilone D (KOS-1584) (196) Oncology Tubulin stabilization Phase PII Kosan (Memorial Sloan-Kettering) 919... 

Paclitaxel (21), formerly known as taxol , is a nitrogen-containing diterpenoid compound isolated from the bark of Taxus brevifolia Nutt. (Pacific yew). As an anticancer agent, paclitaxel acts as a tubulin stabilizer and leads to cell cycle arrest.Since paclitaxel was originally isolated from the bark of the slow-growing species, 77 brevifolia, sourcing was a major obstacle in the development of this drug and its introduction into the market.However, as described later in this chapter, this has now been overcome. 

Ramaswamy B, Puhalla S. Docetaxel a tubulin-stabilizing agent approved for the management of several solid tumors. Drugs Today (Bare) 2006 42(4) 265-279. 

Several natural products, such as epothilones, discodermolide, and eleutherobin, were found to have a similar mechanism of action as paclitaxel. A recent review outlined many tubulin stabilization natural products and their analogs as anticancer... 

With the identification of the myxobacterial products epothilones A and B (64, 65 Figure 12) as tubulin stabilizers (a similar mechanism to that of paclitaxel) by Bollag et in 1995 came a veritable avalanche of modifications of the base structure by chemical, biochemical, and even genomic means in order to further explore the utility of the base skeleton. This culminated in the approval in October 2007 by the FDA of the semisynthetic epothilone, 16-aza-epothilone B, known genetically as ixabepilone (66, Figure 12 Ixempra) for treatment of breast cancer. 

The initial identification by Reichenbach and Hdfle of the 16-membered macrolides epothilones A and B (Figure 1.6, 56 and 57) from Sorangium cellulosum So ce90, is covered in detail in reviews by Reichenbach and H6fle. ° These discoveries, coupled to the report of their activity as tubulin stabilizers in 1995 by workers at Merck, led to work in the USA and Germany on the production of these molecules and other variations from bioengineered organisms. 

MTs are stabilized at their minus ends by the centrosome (also called microtubule organizing center, MTOC). Centrosomes are protein complexes containing among other proteins two centrioles (ringlike structures) and a-tubulin. Centrosomes serve as nucleation points for microtubular polymerization and constrain the lattice structure of an MT to 13 protofila-... 

Another drug is taxol, which is extracted from the bark of the Pacific yew tree, Taxus brevijolia. Unlike colchicine and the vinca alkaloids, taxol binds tightly to microtubules and stabilizes them against depolymerization by Ca. It also enhances the rate and yield of microtubule assembly, thereby decreasing the amount of soluble tubulin in the cytosol pool. Again, the overall effect of taxol is to arrest dividing cells in mitosis. Taxol is used in cancer chemotherapy. 

Platinum analogs Produce intra- and interstrand cross-links and DNA adducts to disrupt DNA replication Taxane agents Stabilize microtubules and prevent de-polymerization of tubulin... 

Docetaxel -semisynthetic taxane stabilizes tubulin polymers leading to death of mitotic cells -bone marrow suppression -nausea and vomiting -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hypersensitivity reactions -fluid retention syndrome -fatigue -myalgias -alopecia (universal)... 

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

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