Taxanes novel

Sampath D, Discafani CM, Loganzo F, Beyer C, Liu H, Tan X, Musto S, Annable T, Gallagher P, Rios C, Greenberger LM. (2003) MAC-321, a novel taxane with greater efficacy than pachtaxel and docetaxel in vitro and in vivo. Mol Cancer Ther 2 873-884. 

Ramanathan RK, Picus J, Raftopoulos H, Bernard S, Lockhart AC, Frenette G Macdonald J, Mehn S, Berg D, Brescia F, Hochster H, Cohn A. (2008) A phase II study of milataxel A novel taxane analogue in previously treated patients with advanced colorectal cancer. Cancer Chemother Pharmacol 61 453-458. 

Garrett CR, Fishman MN, Rago RR, Williams CC, Dellaportas AM, Mahany JJ, Lush RM, Dalton WS, Gollerkeri A, Cohen MB, Sullivan DM. (2005) Phase 1 study of a novel taxane BMS-188797 in adult patients with solid malignancies. Clin Cancer Res 11 3335-3341. 

Gastrointestinal Head and Neck Metastatic Disease Novel Taxanes Conclusion References... 

Rose WC, Fairchild C, Lee FY. Preclinical antitumor activity of two novel taxanes. Cancer Chemother Pharmacol 2001 47(2) 97-105. 

Menendez A, Laidlaw J, Raventos-Suarez C, et al. In vitro characterization of BMS-184476, a novel taxane with promising preclinical activity. Proc Am Assoc Cancer Res 2000 41 554 (abstract 3529). 

Ferlini C, Distefano M, Pignatelli F, et al. Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors. BrJ Cancer 2000 83(12) 1762-1768. 

Tortora G, Caputo R, Damiano V, et al. Specific Inhibition of EGFR Tyrosine Kinase with ZD1839 ( Iressa ) Combined with a Protein Kinase a Antisense and the Novel Taxane IDN5109 Causes Cooperative Inhibition of Tumour Growth and Angiogenesis. Proceedings of the AACR, Vol. 42, March 2001. abstract 4315. 

Table 6.13 summarizes the novel taxane structures identified with LC/MS. These impurities incorporate several consistent structural variations from the five profile groups of paclitaxel (Figure 6.29). Nearly all of the compounds contain the characteristic paclitaxel... 

TABLE 6.13 Novel taxane structures and related derivatives identified by using paclitaxel as a structural template... 

Gmol, D. J. Bernd, J. Phippard, A. E. Ojima, I. Bernacki, R. J. The use of a novel taxane-base p-glycoprotein inhibitor to identifiy mutations that alter the interaction of the protein with paclitaxel. Mol. Pharmacol., 2001, 60 104—113. 

Mastalerz H, Cook D, Eairchild CR, et al. The discovery of BMS-275183 an orally efficacious novel taxane. Bioorganic and Medicinal Chemistry 11(2), 4315, 2003. 

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

Shionoya M, Jimbo T, Kitagawa M, Soga T, Tohgo A. (2003) DJ-927, a novel oral taxane, overcomes Pglycoprotein-mediated multidrug resistance... 

Ono C, Takao A, Atsumi R. (2004) Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol Pharm Bull 27 345-351. 

Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

Trump DL, Egorin M, Ramanathan R, et al. A novel oral taxane (BMS-275183) a phase I trial with evaluation of pharmacokinetics, pharmacodynamics and bioavailability. 

Straubinger, R. M. A. Sharma, U. S. Sharma, and S. V. Balasubramanian. 1995. Pharmacology and antitumor effects of novel Paclitaxel formulations. In Taxane Anticancer Agents, George G. I. et al., eds. ACS Symposium Series 583. Washington, DC American Chemical Society 111-123. 

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. 

In summary, the T-taxol conformation is the only one that is compatible with the EC density and with the intemuclear distances measured by REDOR ss-NMR. The conformation of T-taxol has been used as a template to design novel bridged taxanes. The fact that some of them possess improved bioactivity [89, 90] provides indirect additional evidence that T-taxol represents indeed the bioactive conformation. 

The combination of structural simplicity of epothilones with respect to paclitaxel, together with their very interesting activity profile appealed different research teams, interested to overcome limitations of taxanes (poor solubility, multi drug-resistance - MDR [61-63]). Investigations on epothilones were focused on the interaction between the ligands and the paclitaxel binding site (as well as the possible similar portions between epothilones and taxanes) in order to find common pharmacopores to be used in activity improvement and design of novel molecules. 

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