Taxane water-soluble

Thbulin-polymerizing chemotherapeutic agents, such as taxanes, have been shown to be one of the most effective drug classes in the treatment of ovarian cancer. The clinical success of paclitaxel has stimulated research into compounds with similar modes of activity in an effort to emulate its antineoplastic efficacy while minimizing its less desirable aspects, which include non-water solubility, difficult synthesis, and emerging resistance. 

Ali et al. reported " the synthesis of a series of C3 -f-butyl paclitaxel analogs with C3 -N amides and carbamates, among which A-debenzoyl-A-(2-thienoyl) analog 12 was the most potent. Although equipotent to docetaxel, and about 25 times more water soluble than paclitaxel, this taxane was not superior to analog 13 reported earlier. 

A typical strategy takes advantage of the limited water solubility of taxanes to partition the compounds between water, and an apolar organic solvent (often a chloro-... 

The medicinal chemistry of taxol indicates that there are three points for esterification on the parent taxane ring system. Both taxol and its active analog taxotere have positions 3 and 10 so occupied. The 7 OH can also be so derivatized to afford active compounds. However, an unesterified C-3 hydroxyl results in an inactive compound. Water-soluble derivatives of C-7 and C-2 have been synthsized as potential pro-drugs to circumvent the extremely poor solubility of the drug. 

FIGURE 16.11 (A) Water-soluble taxane 40. (B) Enantioselective enzymatic hydrolysis of... 

Low water solubility is a significant drawback to the therapeutic utility of the taxanes. This is particularly true of paclitaxel, which has a more lipophilic acetate moiety at Cio compared to docetaxel s more polar hydroxyl group. Paclitaxel must be administered in a vehicle of 50% alcohol/50% polyoxyethylated caster oil, which can lead to an enhanced risk of hypersensitivity reactions (dyspnea, hypotension, angioedema, and uticaria)... 

Due to the poor solubility of Paclitaxel, various groups have developed taxane analogs with greater aqueous solubility. Taxane 9 (Figure 11.2) is a water soluble taxane derivative which when given orally was as effective as i.v. Paditaxd in five tumor models [40]. The chiral intermediate (3P-cis)-3-acetyloxy-4-(l,l-dimethylethyl)-2-azetidinone, (J )-IO was prepared for the semisynthesis of... 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

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