Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI
Graphical abstract
From 1-deoxybaccatin VI, 16e based on the 9,10-carbonate taxane skeleton exhibits 7-fold more potent than paclitaxel in A549/T.
Introduction
Paclitaxel (PTX) 1, a diterpenoid natural compound isolated from the stem bark of Taxus brevifolia (Pacific yew) in 1971,1, 2 and its derivative docetaxel 2 approved by FDA to treat breast cancer in 1996 are active against a number of cancer types including breast, lung, prostate, ovarian and some leukaemias,3, 4, 5 due to their unique mechanism of action by bonding tubulin, promoting microtuble assembly and stabilizing microtubules,6 which ultimately disrupts mitosis and causes cell death.7, 8, 9 However, difficulties related to formulation and multiple drug resistance (MDR) limit the application of paclitaxel and its close analogue docetaxel in cancer treatments.10 Therefore, it is essential to develop novel taxoid anticancer drugs with fewer side effects, superior pharmacological properties and improved activity against various classes of cancers.11, 12, 13
The bioactive conformation of paclitaxel is important since it could provide critical information that would allow the design of novel analogues with simpler structures and increased potency against cancers.14 A series of analogues, which bear a 1,14-carbonate moiety, exhibited improved clinical properties such as oral bioavailability and broader spectrum of antitumor activity. Ortataxel 3 (Fig. 1) not only exhibited two orders of magnitude better cytotoxicity than paclitaxel against drug-resistant cells but also a significant improvement in water solubility, and it has been selected for clinical development.15 In addition, it has been proposed that the ability of C-10 taxane analogues to overcome MDR in vitro is the result of reduced binding affinity for P-glycoprotein such as cabazitaxel 4.16 In 2002, C-9 and C-10
modified taxane analogues 5, 6 and 7 were reported to be similar17 and more potent than docetaxel, respectively.18 These results suggest that substitutions at C7-C10 positions and carbonate group at C-1, C-14 positions may have profound influence on antitumor activity. Thus further exploration of the effects of carbonate group at C-9 and C-10 positions could be fruitful for the discovery of new candidates for drug development.
1-Deoxybaccatin VI (8), which is extracted from roots of Taxus chinensis in relatively high yield and reserves the essential pharmacophore, proves to be the valuable starting material for research.19, 20 As an ongoing part of our research on taxane analogues,21, 22 we developed a series of 1-deoxypaclitaxel analogues 16a-h bearing different substituted groups at the C-3′-N-acyl position, C-7, C-9 and C-10 positions from 1-deoxybaccatin VI. The activities of these newly synthesized compounds against three cancer cell lines and cell survival data are also reported in this paper.
Section snippets
Chemistry
As shown in Scheme 1, selective deacetylation of the C-7, C-9, C-10 and C-13 acetoxyl groups without concomitant deacylation of the C-2 and C-4 acyloxy groups of 1-deoxybaccatin VI 8 afforded 9. Subsequent carbonation of the C-9 and C-10 hydroxyl groups using carbonyldiimidazole (CDI) gave compound 10 due to the smaller stereo-hindrance effect on the C-9 and C-10 hydroxyl groups compared with C-7 and C-9 hydroxyl groups, in which only two hydroxyls remained at the C-7 and C-13 positions. The
Conclusion
In summary, we have synthesized 1-deoxy taxane analogues from 1-deoxybaccatin VI and found that analogue 16e based on the 9,10-carbonate taxane skeleton exhibits comparable cytotoxicity in A549 cell-based assay relative to paclitaxel and shows 7-fold more potent than paclitaxel in the A549/T assay. The new toxoids bearing different substituted groups at C-3′-N position showed degrees of cytotoxicity. Most of the compounds exhibited greater inhibition of cell survival than paclitaxel in
General chemical procedures
Commercially available reagents were purchased and were used without further purification unless otherwise mentioned. 1H NMR and 13C NMR spectra were recorded on a Bruker DM-500 MHz spectrometer at 500.134 MHz and 125.771 MHz, respectively, with TMS as an internal standard. Chemical shifts are reported in parts per million (ppm) and coupling constants (J) are reported in Hertz (Hz). Coupling patterns are described by abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet) and br
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank Drs. H.M. Deng and M. Shao, The Instrumental Analysis& Research Center of Shanghai University, for structural analysis. This work was in part supported by National Natural Science Foundation of China (Nos 21272154 & 81202402) and Science and Technology Commission of Shanghai Municipality (No 19ZR1419700).
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