Taxoids/taxanes

The metabolism of taxol by Eucalyptus perriniana cell suspension cultures has been recently reported to induce hydrolyses of ester bonds at C-13, C-10 and C-2 [222]. At this moment only very few data have been published about the microbial metabolism of taxoid compounds only site specific hydrolyses of acyl side-chains at C-13 or C-10 by extracellular and intracellular esterases of Nocar-dioides albus SC13,911 and N. luteus SC13,912, respectively, have been reported [223]. On the other hand, Hu et al. [224-226] have recently described some fungal biotransformations of related natural taxane diterpenes extracted from Chinese yews or their cell cultures, in order to obtain new active substances or precursors for hemisynthesis. The taxadiene 145, a 14 -acetylated derivative... 

In the course of our study on the rational design, synthesis and SAR of new antitumor taxoids, we became interested in incorporating fluorine(s) into paclitaxel and taxoids in order to investigate the effects of fluorine on cytotoxicity, blocking of known metabolic pathways, and its use as a probe for identifying bioactive conformation(s) of taxane antitumor agents. 

Sometimes natural taxanes or synthetic taxoids exhibited unexpected cytotoxicities, which may provide new clues for SAR. Because m-azido baccatin 111 103 was found to be almost as comparably active as paclitaxel, 7-deoxy-9,10-O-acetylbac-catin 104 was prepared from taxinine 105, a plain and abundant inactive taxane from T. cuspidata. Both 104a and 104b were found to be inactive (IC50 at 10 M level). ... 

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... 

Research by S. Arseniyadis and co-workers showed that the aldol-annelation-fragmentation strategy could be used for the synthesis of complex structures, which are precursors of a variety of taxoid natural products.This strategy allows the preparation of the twenty-carbon framework of taxanes from inexpensive and simple starting materials. 

A few main subclasses can accommodate most alkaloids, and a system of nomenclature based on names defined in the literature can avoid the confusing use of very similar trivial names that plague the literature on taxoids. Thus, taxine B is a taxane alkaloid [24], whereas taxin B is a non-nitrogenous 2(3->20)abeotaxane [33]. 

Two taxane alkaloids have been investigated by diffraction techniques taxine A (la) [23] and 2 deacetoxyaustrospicatine (41) [49], The results gave important information on the orientation of the side chain relatively to the terpenoid core. In both cases the aromatic ring is close to the terpenoid core, but in 4f the phenyl and the catbonyl are antiperiplanar, whereas in taxine A they are synclinal (cf. C and A in Scheme 3). As a result, the protons closer to the phenyl ring are H(6a) in taxine A and H(14a) in 4f. This is in accordance with the results of the H-NMR analysis [46], In 4f, the conformation with C-l and the phenyl antiperiplanar is stabilized by hydrophobic interactions with the methyl of the 13-acetate [49], The X-ray features of the terpenoid core of 4f and taxine A show linear strain at several carbon-carbon bonds, as generally observed in taxoids [55]. 

Paclitaxel and docetaxel are taxane plant alkaloids with antimitotic activity (see Table 124-12). Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia, but is now produced semisyntheti-cally from the needles of the European yew, Taxus baccata. Docetaxel is a semisynthetic taxoid extracted from 10-deacetyl baccatin III, a noncytotoxic precursor found in the renewable needle biomass of yew plants. ... 

A number of taxoids isolated from different Taxus species, on structural reinvestigation were found to contain a rearranged nortaxoid skeleton or 11(15—>V)-abeo taxoids, as they are more correctly described (133,160,161) and not a taxane skeleton as originally proposed. Brevifoliol (181) was the first natural taxoid with 11(15—>l)-afoeotaxane skeleton which was initially assigned a normal taxane skeleton (162) but was later corrected to the... 

These compounds have a distinct biogenetic origin than the other taxoids, resulting from a transannular cyclisation, which is different from that involved in the formation of normal taxanes (92). They are tricyclic systems with a ten membered ring sandwiched between two six membered rings. Isolates of this class from Taxus species are listed in Table 4. 

In order to isolate the actual promoter(s), the crude extracts were further resolved by a series of chromatographic separations. The methanol soluble extract was subjected to LH-20 size exclusion chromatography (methanol). Twelve fractions eluted and almost all activity was concentrated in fraction B . TLC analysis indicated that this material was identical to the G fraction previously tested. Table 7 shows the taxoid titers of P. raistrickii cultures grown with these column fractions (experiment 8-50). The results show taxol and taxane titers of combined mycelial and filtrate extracts minus background. Fungi were grown for 6 days, shaken at 200 rpm, room temperature, in M-l-S broth (soytone sucrose and yeast). All results were extrapolated to ng/L. 

Varying concentrations of colchicine were added to cultures of P. raistrickii H10BA2 in experiment 7-129. Contrary to expectations, mycelial growth was unusually luxuriant. Each culture was extracted and assayed for taxoid titers as usual. Table 8 shows these results for the chloroform extracts of the media. Colchicine appeared to augment fungal growth and induce taxol/taxane production. These numbers were reasonably impressive and consistent in repeated experiments. 

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