Taxane analog

Advani R, Fisher GA, Lum BL, Jambalos C, Cho CD, Cohen M, Gollerkeri A, Sikic BI. (2003) Phase 1 and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies. Clin Cancer Res 9 5187-5194. 

The success of taxane-based therapy in cancer treatment has stimulated interest in further improving its efficacy profile and in identifying new tubulin-active agents. Two taxane analogs, BMS-184476 and BMS-188797, demonstrate greater activity than paclitaxel or docetaxel in a number of human tumor cell lines as well as in rodent solid tumors and human xenografts (4,145). BMS-184476 was discovered to be more potent... 

Highely M, Sessa C, Hughes A, et al. Phase I and pharmacokinetic (PK) study of BMS-184476, a new taxanes analog, given weekly in patients with advanced malignancies. Proc Am Soc Clin Oncol 1999 18 168a (abstract 644). 

Stevenson JP, Gallagher M, Sun W, et al. Phase I clinical and pharmacokinetic study of the taxanes analog BMS-184476 administered as a 1-hour iv infusion in combination with carboplatin every 21 days. Proc Am Assoc Cancer Res 2000 41 608 (abstract 3871). 

Extensive structure-activity relationship (SAR) studies have led to many related antineoplastic taxane analogs, including ortataxel (B4), an orally administered taxoid in Phase It chnical... 

R. Plnmmer, M. Ghielmini, P. Calvert, M. Voi, J. Renard, G. Gallant, E. Gupta, H. Calvert, and C. Sessa, Phase I and pharmacokinetic stndy of the new taxane analog BMS-184476 given weekly in patients with advanced malignancies. Clin Cancer Res 8 2788-2797 (2002). 

Coordination polymer 54 prepared from the ligand 53 andAgNOs a one single chain b polyro-taxane analogous layer of different chains c schematic representation of the structure. 

Klein LL, Maring CJ, Li L, Yeung CM, Thomas SA, Grampovnik DJ, Plattner JJ, Henry RF (1994) Synthesis of Ring B-Rearranged Taxane Analogs. J Org Chem 59 2370... 

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... 

Scheme 11.8 Metathesis results on the synthetic approach to taxane analogs. 11.3.3...

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... 

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. 

Tasquinimod (structure shown in Fig. 4) is a second-generation orally active quinoline-3-carboxamide analog with enhanced potency against prostate cancer via its antiangiogenic activity. It is presently undergoing clinical trials [35]. Androgen ablation and taxanes are standard therapies for metastatic prostate cancer [36]. 

Amiodarone Chloroquine Cisplatin Colchicine Dapsone Disulfiram Glutethimide Gold compounds Hydralazine Isoniazid Misonidazole Nitrous oxide Nitrofuratoin Nucleoside analogs (antiretrovirals) Paclitaxel (taxanes) Phenytoin... 

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. 

---