Taxoid natural products

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. 

Hamel, E., Sackett, D. L., Vourloumis, D., and Nicolaou, K. C. (1999). The coral-derived natural products eleutherobin and sarcodictyins A and B Effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry 38, 3490-3498. 

The attainment of this pocket by quite different structural motifs indicates that the pocket on (3-tubulin may be malleable and its moulding by natural product ligands may be the key to unravelling the mechanisms of tubulin assembly.61 As taxoids and epothilones have proven successful in the clinic,62,63 advancing the understanding as to the mechanisms involved in regulating... 

The high loading capability of large-volume CCC systems is commonly used in industry. Large amounts (gram to kilogram scale) of natural products with high added values are separated by CCC. Alkaloids, antibiotics, enzymes, macrolides, peptides, rare fatty acids, saponins, tannins, taxoids and/or precursors of Taxol , and other fine chemicals have been isolated, separated, and/or purified by preparative CCC [1]. 

Holt and co-workers used olefin metathesis to synthesize a number of enantiomerically pure aimulated carbohydrate systems containing carbocycles, as precursors for the synthesis of taxoids and other natural products. Treatment of dienes 146 and 148 with a catalytic amount of 3 in benzene gave the corresponding 6,6,6-carbocycles, cis-147 and trans-149, in 89 and 80% yield, respectively. The authors attempted a similar strategy to prepare 6,6,5-annulated systems however, they achieved little to no yield of the desired products, presumably due to ring strain. Holt and co-workers... 

Historically, building up a library around a given core structure has been the first strategy to access natural product libraries. This approach is still the preferred way to prepare either focused libraries to study the SAR of certain natural products or to build libraries of very complex natural product scaffolds which cannot be constructed on solid phase yet. In Fig. 1 two notable structures of natural product libraries built by core structure modification are highlighted, such as an Indolactam library by Waldmann [72], and a Taxoid library by Xiao [73]. 

In an illustration of the degree of functionality and structural complexity this reaction can accept, a number of macrocyclic taxoid derivatives (46, Figure 11.6, site of cyclization indicated along with the catalyst employed using the designations in Figure 11.5) were synthesized using RCM and assisted in the determination of the active conformation of this class of anticancer natural products. 

Repeated chromatographic separations of the yew extract, followed by fungal fermentations using these individual components as media amendments, indicated that specific compounds were responsible for higher taxoid production levels. CIEIA analysis of these yew components indicated that these titer promoters are not taxoid in nature. 

Paclitaxel (Taxol, NSC-125973), obtained from Taxus species, is a diterpene with intense antitumoral activity because of its tmique mode of action on the microtubular cell system. It is one of the most successful anticancer drugs developed in the past 50 years. Due to several difficulties associated with obtaining Taxol and related taxoids firom plants growing in nature, plant cell cultures are considered to be the most favorable and environmentally sustainable approach for its production of at an industrial level. Some pharmaceutical companies, such as the... 

Paclitaxel (Taxol) 57, a natural terpenoid product derived from the bark of the Pacific yew Taxus brevifolia [83-85], and its hemisynthetic analog docetaxel (Taxotere) 58, are two recently discovered promising antitumor agents. At this moment, 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 Nocardioides albus SC 13911 and N. lutea SC 13912, respectively, have been reported [86]. On the other hand, Hu et al. [87-89] recently described some fungal biotransformations of related more abundant natural taxane diterpenes extracted from Chinese yews or their cell cultures, in order to obtain new active substances or precursors for hemisyn-thesis of paclitaxel analogs. 

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