Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Mar 27;72(3):554-65.
doi: 10.1021/np8006556.

Recent advances in the chemistry and biology of new generation taxoids

Iwao Ojima  1 , Manisha Das
Affiliations
Review

Recent advances in the chemistry and biology of new generation taxoids

Iwao Ojima et al. J Nat Prod. .

Abstract

Among the numerous chemotherapeutic drugs, paclitaxel and docetaxel are among the most widely used against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop "taxane" anticancer agents with better pharmacological properties and improved activity especially against drug-resistant cancers. Several laboratories have performed extensive SAR studies on paclitaxel. Our SAR studies have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3' positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the new generation taxoids also exhibited excellent cytotoxicity against pancreatic cell lines expressing multidrug-resistant genes. We have also designed taxoids with strategic fluorine incorporation to investigate their effects on the cytotoxicity and the blockage of known metabolic pathways. Furthermore, we have successfully employed computational biology analysis to design novel macrocyclic taxoids to mimic the bioactive conformation of paclitaxel. This account describes our work on the design, synthesis, and biological evaluation of these novel taxoids, which has led to the discovery of very promising candidates for further preclinical studies.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Figure 2
Figure 2
Primary sites of hydroxylation on the second-generation taxoids by the P450 family of enzymes
Figure 3
Figure 3
Designed novel C-14-C-3′BzN–linked macrocyclic taxoids
Figure 4
Figure 4
Overlays of REDOR-Taxol (green) with 34a (cyan), 34b (red) and 34c (pink).
Figure 5
Figure 5
X-ray crystal structure of 43b (SB-T-2054)
Figure 6
Figure 6
Tubulin polymerization with 43b and paclitaxel: microtubule protein 1mg/mL, 37 °C, GTP 1 mM or Drug 10 μM
Figure 7
Figure 7
Overlays of REDOR-Taxol (green) with 43b (SB-T-2054) (purple).
None
Scheme 1
Reagents and conditions: (i) (a) TESCl, imidazole, (b) LiHMDS, AcCl, 95% in two steps; (ii) LiHMDS, THF, 95%; (iii) N2H4·H2O, EtOH, 85%
None
Scheme 2
Reagents and conditions: (i) (a) RCl, TEA, DMAP, CH2Cl2 or (b) ROH, DIC, DMAP, CH2Cl2 or (c) RCl, LiHMDS, THF, -20 °C (75-98%); (ii) HF/pyridine, pyridine/MeCN (80-97%).
None
Scheme 3
Reagents and conditions: (i) TESCl, imidazole, DMF, RT, 96%; (ii) sodium bis(2-methoxyethoxy)aluminumhydride, THF, -10 °C, 97%; (iii) DIC, DMAP, CH2Cl2, 85-90%; (iv) HF/pyridine, pyridine/MeCN; (v) TESCl, imidazole, DMF, RT, 2 h 71-95% for two steps; (vi) LiHMDS, R2COCl, THF, 67-98%.
None
Scheme 4
Reagents and conditions: (i) 3a-f (1.2∼1.5 eq), LiHMDS, THF, -40 °C, 30 min; (ii) HF/pyridine, pyridine/MeCN, 0 °C – RT, 18 h, 65-95% for two steps; (iii) H2/Pd-C, EtOAc/MeOH, RT, 24 h, 70-89%.
None
Scheme 5
Reagents and conditions: (i) LiHMDS, THF, -40 °C, 30 min; (ii) HF/pyridine, pyridine/MeCN, 0 °C – RT, 18 h (61-86% for two steps); (iii) H2, Pd/C, EtOAc, RT, 24 h (95-98%).
None
Scheme 6
None
Scheme 7
Reagents and conditions: i) Cu(OAc)2, MeOH, 77-86 %; ii) l-selectride, THF, -78 °C 50-70%, iii) methyl imidazole, TESCl, DMF, 0 °C, 50-80 %; iv) LiHMDS, THF, -40 °C, 70-80%; v) HF/pyridine, CH3CN/pyridine, 0 °C - RT, 52%-92%.
None
Scheme 8
Reagents and conditions: i) CBr2F2, HMPT, Zn, THF, 84%; ii) CAN, H2O/CH3CN, -15 °C, 92%; iii) Boc2O, Et3N, DMAP, CH2Cl2, 96%; iv) LiHMDS, THF, -40 °C, v) HF/Py, Py/CH3CN, overnight, 0 °C-RT, 57-91%.
None
Scheme 9
Reagents and conditions: (i) acid chloride (2.0 equiv.), Et3N (4 equiv.), CH2Cl2, DMAP, overnight.
None
Scheme 10
Reagents and conditions: (i) (a) Ac2O (10 eq), CeCl3·7H2O (0.1 eq), THF, r.t., 2 h, (b) TESCl (3.0 eq), Imidazol (4.0 eq), DMF, r.t., 5 h (83% in 2 steps), (ii) Allyl iodide (1.1 eq), NaHMDS (1.1 eq), DMF, -40 °C, 1 h (82%), (iii) 37a-d (3.0 eq), LiHMDS (1.5 eq), THF, -30 °C ∼ 0 °C, 2.5 h.
None
Scheme 11
Reagents and conditions: (i) (a) Cl2Ru(=CHPh)(PCy3)2 (0.2 eq), CH2Cl2, overnight; (ii) HF/Py, Py, CH3CN, r.t., overnight
None
Scheme 12
Reagents and conditions: (i) (a) Cl2Ru(=CHPh)(PCy3)2 (0.2 eq), CH2Cl2, overnight, flash chromatography; (ii) HF/Py, Py, CH3CN, r.t., overnight.
None
Scheme 13
Reagents and conditions: (i) (a) Cl2Ru(=CHPh)(PCy3)2 (0.25 eq × 3), CH2Cl2, reflux, 5d; (ii) HF/Py, Py, CH3CN, RT, overnight
See this image and copyright information in PMC

References

    1. Jemal A, Ward E, Hao Y, Thun M. J Am Med Assoc. 2005;294:1255–1259. - PubMed
    1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. CA: Cancer J Clin. 2006;56:106–130. - PubMed
    1. Rowinsky EK. Ann Rev Med. 1997;48:353–374. - PubMed
    1. Suffness M. Taxol: Science and Applications. CRC Press; New York: 1995.
    1. Schiff PB, Fant J, Horwitz SB. Nature. 1979;277:665–667. - PubMed