Paclitaxel analogs synthesis

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. 

The ability to access bridged-ring systems is exemplified by the efficient conversion of diazene 59 to cycloadduct 60. It is noteworthy that the conversion can routinely be carried out on a 20 g scale [25]. This chemistry was explored in conjunction with the development of a route to a paclitaxel analog (61) (Scheme 8), and is currently being examined as a key step in the development of a synthesis of aphidicolin ]26]. 

Liang X, Kingston DGI, Lin CM, Hamel E (1995) Synthesis and Biological Evaluation of Paclitaxel Analogs Modified in Ring C. Tetrahedron Lett 36 2901... 

Chen S-H, Xue M, Huang S, Long BH, Fairchild CA, Rose WC, Kadow JF, Vyas D (1997) Structure-Activity Relationships Study at the 3 -N Position of Paclitaxel-Part 1 Synthesis and Biological Evaluation of the 3 -(0-Butylaminocarbonyloxy Bearing Paclitaxel Analogs. Bioorg Med Chem Lett 7 3057... 

Yuan H, Kingston DGI (1999) Synthesis and Biological Activity of a Novel C4-C6 Bridged Paclitaxel Analog. Tetrahedron 55 9707... 

SCHEME 3.35. Solid-phase synthesis of paclitaxel analogs. 

Synthesis of paclitaxel and resiniferatoxin analogs, diterpenoids with oxetane fragments 97G461. 

The synthesis of heteroaromatic side-chain analogs masked as P-lactams of paclitaxel was efficiently accomplished by a cyclocondensation strategy between sultam-modified ester enolates and imines, demonstrating yet another strategy in sultam-enolate chemistry [26],... 

Liu et al. reported in 2003 on the synthesis and cytotoxicities of 3 -cyclopropane analogs with both Tot- and 7(3-OH and 2 R)- and 2 (5)-OH functionalities. Both 2 - R) isomers were 400 times less active than paclitaxel in A2780 cancer cell assays, and 2 -(5) isomers displayed even weaker cytotoxicities. Unsatisfactory results may have developed from small volumes of the 3 -cycloprapane, which is similar to 3 -methyl in 9(R)-dihydro paclitaxels as reported earlier. As mentioned, larger groups such as isobutyl or isobutenyl may interact with the receptor better. 

Yuan et al. have reported on the synthesis of a C-ring contracted analog (90) from 2 -TBS-6a-OH-7-ep/-paclitaxel (89), upon the treatment of lead tetraacetate. After 2 -desilylation, the analog 91a showed 10 times reduced activity, and its 7-Ac derivative 91b was even less active. " ... 

The similarity in the mechanisms of action of paclitaxel (Section 1.1), the epothilones (Section 1.3), discodermolide and eleutherobin (section 1.2) has led to proposals that these structurally dissimilar substances possess common pharmacophores which could lead to the design and synthesis of analogs having substantially different structures and superior activities. 

Efforts to get access to improved manufacturing processes or improved application properties of paclitaxel resulted in two different pathways for the total synthesis of the natural product, as well as analogs. Furthermore, paclitaxel and/or precursors can be obtained under optimized conditions from cell cultures of Taxus media generated by hybridizing Taxus baccata and Taxus cuspidata in overall yields of about 130 mg 11 within two weeks [61]. Paclitaxel can also be obtained by the culture of appropriate microbial strains isolated from paclitaxel producing yew trees [62 - 64]. 

The success of paclitaxel spurred an enormous amount of work on the synthesis of analogs, and this work has been summarized in several reviews. The first analog to be developed is the close chemical relative, docetaxel (Taxotere Figure 8.13). The new albumin-bound formulation of paclitaxel known as Abraxane has also been approved for clinical use and launched in 2005 this formulation offers some important clinical advantages compared with the original Cremophor formulation. The reviews cited above should be consulted for information on new agents in development, such as BMS-184776, BMS-188797, and larotaxel (Figure 8.13). 

E., Synthesis and biological evaluation of novel paclitaxel (Taxol) D-ring modified analogs, J. Org. Chem. 64 (8), 2694, 1999. 

Enzymes were used for the chiral synthesis or resolution of side chains that can be coupled to 10-deacetylbaccatin 111 in the semisynthesis of paclitaxel and analogs. Racemic acetate 8 (Scheme... 

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