Research Advances in Clinical Applications, Anticancer Mechanism, Total Chemical Synthesis, Semi-Synthesis and Biosynthesis of Paclitaxel

Abstract

Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the Taxus tree, is considered one of the most successful natural anticancer drugs due to its low toxicity, high potency and broad-spectrum anticancer activity. Taxus trees are scarce and slow-growing, and with extremely low paclitaxel content, the contradiction between supply and demand in the market is becoming more and more intense. Therefore, researchers have tried to obtain paclitaxel by various methods such as chemical synthesis, artificial culture, microbial fermentation and tissue cell culture to meet the clinical demand for this drug. This paper provides a comprehensive overview of paclitaxel extraction, combination therapy, total synthesis, semi-synthesis and biosynthesis in recent years and provides an outlook, aiming to provide a theoretical basis and reference for further research on the production and application of paclitaxel in the future.

Keywords: anticancer mechanism; biosynthesis; paclitaxel; semi-synthesis; total synthesis.

Figure 1

The structure of paclitaxel.

Figure 2

Mechanism of action of paclitaxel on microtubulin.

Figure 3

The structures of paclitaxel-like compounds.

Figure 4

Summary of the eight-membered ring synthetic strategy of paclitaxel [53,54,55,56,58,59,60,61,62,63,64,65,66,67,68,69,70].

Figure 5

BMS company’s synthetic route for paclitaxel and common types of paclitaxel semi-synthetic side chains [57,73].

Figure 6

Synthesis of linear phenylisoserine side chains [74].

Figure 7

Synthesis of β-lactam tetracyclic side chains [74].

Figure 8

Synthesis of oxazolidine pentacyclic side chains [74,75].

Figure 9

Semi-synthesis of paclitaxel from 10-deacetyl-7-xylosyltaxanes and 10-deacetyl paclitaxel-7-xyloside [77,78].

Figure 10

The biosynthetic pathway of paclitaxel. Enzymes in red are not yet characterized, and steps in red dotted arrows are not yet fully elucidated. Enzyme abbreviations: TS, taxadiene synthase; T5αH, taxane-5α-hydroxylase; TAT, taxane-5α-ol-O-acetyltransferase; T10βH, taxane-10β-hydroxylase; T13αH, taxane-13α-hydroxylase; T1βH, taxane 1β-hydroxylase; T9αH, taxane 9α-hydroxylase; T9αO, taxane 9α-dioxygenase; T2αH, taxane 2α-hydroxylase; T7βH, taxane 7β-hydroxylase; C4-C20, C4-C20 epoxidase; TBT, taxane-2α-O-benzoyl transferase; DBAT, 10-deacetylbaccatin III-10-O-acetyltransferase; PAM, phenylalanine aminomutase; PCL, phenylalanine-CoA ligase; BAPT, C-13 phenylpropanoyl-CoA transferase; T2′αH, taxane 2′α-hydroxylase; DBTNBT, debenzoyl taxol N-benzoyl transferase; ACT, acyl-CoA transferase.

Figure 11

One-pot reaction system for the bioconversion of XDT to paclitaxel. The system contained a specific 7-β-xlyosidase, the improved 10-β-acetyltransferase, the substrate XDT and the acetyl group donor acetyl-CoA [180].