Docetaxel analogs

The extension of the C-13 side chain to its homologated one furnished poorly active paclitaxel and docetaxel analogs in tubulin assembly assay. The authors assumed that the poor activity of the analogs may have originated from their different conformations from that of paclitaxel in water. 

The SAR results for many other 14(3-OH paclitaxel and docetaxel analogs were scattered in different parts in Section 3.2, for example, the results in Refs. 20, 54,... 

From properly protected 19-hydroxy-10-DAB 58, a natural taxane, its docetaxel analog 59 was obtained by the acid approach, which was proven to be active in promoting tubulin polymerization ability as well as cytotoxicity. ... 

Synthesis of a 2a-N substimted analog 2-debenzoyloxy-2a-benzamido docetaxel analog 65a was realized as the first example in the preparation of 2a-heteroatom linkages in our laboratory recently. The key step for the synthesis is transformation of 2(X-baccatin 64a to 2a-azido baccatin 64b through a double Sn2 conversion. The... 

DBU and silica gel in 1,2-dichloroethane, respectively.Paclitaxel and docetaxel analogs with 7a-F are not superior to the parent compounds in both in vitro and in vivo, and those with 7,19-cyclopropane and 6,7-olefin were comparably active. ... 

In the early 1990s, the Bartons protocol was widely applied to the preparation of deoxygenated derivatives at many sites on taxanes. Enhancement of cytotoxicity was observed for many 7-deoxy paclitaxel and docetaxel analogs, along with a... 

Bourchard et al. attempted to reduce the 7,19-cyclopropane docetaxel analog 92a electrochemically. Besides the major 10-deoxy product 92b, C-ring expanded 19-nor analog 93 was obtained as a minor product. Taxoid 93 did not exhibit any activity in both cytotoxicity and tubulin binding assays, although its conformation is analogous to that of docetaxel. 

In 2002, it was found that a 2-diflurobenzoyl paclitaxel analog (60d) exhibited comparable activity with paclitaxel, are best in C-2 mono- and di-substituted benzoyl analogs and better than 9a and 9b in paclitaxel-resistant HCT-116/VM46 cancer cell lines. It was also reported that some 2-debenzoyloxy-2a-benzamido docetaxel analogs were comparably cytotoxic with paclitaxel toward some drug-resistant tumor cell lines. 

A group from Daiichi Co. reported many 9(3-dihydro-paclitaxel and docetaxel analogs, including 47, 49, and 50a-b, which exhibited significant antitumor effects in vitro and in vivo against MDR mmors. Some of them were also highly water soluble as well as orally active. 

DJ-927 (49), a 9-dihydro-7-deoxy docetaxel analog under its phase 1 clinical trial, was effective against various mmors, especially P-gP overexpressing MDR tumors in vivo. Additional investigation showed that it is not a P-gP substrate and its cytotoxicity is not influenced by P-gP modulators. Although the authors proposed that the effectiveness of DJ-927 may be partly from higher intracellular accumulation, its mechanism against MDR tumors should be addressed in the fumre. ... 

A later publication from the Potier group described a synthesis of the side chain derivative of 2.1.7. The secret to attaching the side chain lay in removing the C-4 acetate group when this was done the 4-deacetyl derivative 2.1.8 could be acylated at C-13 and then derivatized to give the docetaxel analog 2.1.9 (35). Disappointingly the C-4 acetate could not be reinstalled, so the fact that compound 2.1.9 was inactive in the microtubule disassembly assay does not prove that the dihydro modification is deleterious to activity. 

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... 

The only reported taxol analog modified at C-19 was prepared from the naturally occurring 10-deacetyl-19-hydroxybaccatin III (3.3.1), Protection of 3.3.1 as its 7,10,19-tri(trichloroethoxycarbonate), followed by coupling with a protected side chain and appropriate deprotection gave the 19-hydroxy docetaxel analog 3.3.2 (103)... 

Reacylation at the C-4 position is also difficult because of the hindered nature of this position, but various methods have been developed to overcome this problem. The first C-4 analog of taxol was reported by Georg, who converted a 2, 7-protected taxol to its 2,4-dideacyl derivative and thence to the cyclic carbonate 4.3.2.I. Esterification at C-4 was achieved with excess isobutyric anhydride and DMAP to give the 4-isobutyrate derivative 4.3.2.2, which was converted to the taxol analog 4.3.2.3 with phenyllithium followed by deprotection. The corresponding docetaxel analog was also prepared (190). 

Functional group transformations of the /3-lactam form of the taxol side chain precursor have also been investigated. For example, both the Ojima and the Georg groups showed that N-(r-Boc) -lactams can be converted to other N-acyl /3-lactams in very good yield without losing optical purity. These transformations allowed preparation of various side chain modified taxol or docetaxel analogs (246, 247, 248). 

Uoto K, Mitsui I, Terasawa H, Soga T (1997) First Synthesis and Cytotoxic Activity of Novel Docetaxel Analogs Modified at the C-18-Position. Bioorg Med Chem Lett 7 2991... 

Bouchard H, Commer on A, Combeau C, Riou JF, Lavelle F (1996) Synthesis of 7,10-Hydroxy-Modified Docetaxel Analogs, 20 lUPAC Symposium on the chemistry of Natural Products, Chicago, Sept. 15-20, Abstract No. SY-9... 

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