14 3-Hydroxy taxoids

Development of the 14(3-hydroxy taxoid series is a highly successful venture as well. We have developed new chemistry and obtained some advanced candidates for clinical trials which may indeed have improved bioavailability and unique tumor specificity profiles. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

P-Hydroxy-10-deacetylbaccatin III (75, 14P-OH-DAB) was first isolated from the needles of the Himalayan yew tree (Taxus wallichiana Zucc.) and its structure was determined by X-ray crystallographic analysis in 1992.93 Because of an extra hydroxyl group at the C-14 position, 14P-OH-DAB (75) has much higher water solubility than DAB (3), the key precursor of paclitaxel and docetaxel. We envisaged that new taxoids derived from 75 would improve water solubility and bioavailability, and also reduce hydrophobicity-related drug resistance. These improved... 

A series of 14p-hydroxy and 14p-acyloxy taxoids 34 with lOp, 5a, 2a-acetoxy, or hydroxy substitutions without C-13 oxygenations and oxetane D ring have been isolated from the cell culture of T. yunnanensis. Attachment of the A-benzoylphe-nyhsoserine side chain to C-14, and incorporation of the 4(20), 5-oxetane ring and change of 2-acetate did not improve their activity. The fact that all derivatives are far less active than paclitaxel prompted the authors to suggest that C-14 isoserine isomers did not bind to tubulin properly. 

Ojima, I., Slater, J. S., Kuduk, S. D., et al. (1997) Syntheses and structure-activity relationships of taxoids derived from 14P-hydroxy-10-deacetylbaccatin IB. Journal of Medicinal Chemistry, 40, 267-278. 

Although direct modification of the C-14 position of the taxoid skeleton has recently proved possible, as noted above (46), most 14-hydroxytax-oids have been prepared from the naturally occurring 14-/3-hydroxy-10-deacetylbaccatin III (2.3.1) (47). Thus Ojima and his collaborators prepared the protected 14y3-docetaxel analog 2.3.2 by protection of the C-10 and C-7 hydroxyl groups as their Troc derivatives, and then of... 

A true taxoid dimer was prepared by Cheng and coworkers by Diels-Alder cyclization of taxinine B and taxacin I derivatives. Thus oxidation of 20-hydroxy-4,5-ene-7-oxotaxinine derived from natural taxinine B... 

Ojima I, Park YH, Sun C-M, Fenoglio I, Appendino G, Pera P, Bemacki RJ (1994) Structure-Activity Relationships of New Taxoids Derived from 14/ -Hydroxy-10-deacetylbaccatin III. J Med Chem 37 1408... 

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