The shape of things to come: structural and synthetic studies of taxol and related compounds

Abstract

The history of the development of Taxol (paclitaxel) as an anticancer drug is reviewed, and some aspects of the phytochemistry of Taxus species and of the medicinal chemistry of taxol are discussed. The nature of the taxol-tubulin interaction is then described, with an emphasis on studies that led to the discovery and experimental proof of the T-taxol conformation as the tubulin-binding conformation of taxol. The implications of this conformation for future drug development are also briefly covered.

Fig. 1

Structure-activity relationships of taxol

Figure 2

The T-taxol conformation, showing the C2 benzoyl group positioned between the two side chain phenyl groups.

Figure 3

Internuclear distance determined by REDOR NMR spectroscopy

Figure 4

The T-taxol conformation, showing the close connection between the C4 acetate group and the 3′ phenyl ring.

Scheme 1

Synthesis of labeled taxol 22.

Scheme 2. Synthesis of β-lactam 27

a. (i) p-MeOC₆H₄NH₂, MgSO₄, CH₂Cl₂ (100%); (ii) CH₃COOCH₂COCl, Et₃N, −78 °C-room temp, 12 h (80–85%); (iii) lipase PS (Amano), phosphate buffer, pH = 7.2, CH₃CN, 24 h - 12d (95–95%) b. (i) 1 M, KOH, THF, 0°C (quantitative); (ii) TIPSCl, imidazole, DMF (90–94%); (iii) CAN, CH₃CN, −5 °C (65–92%) c. PhCOCl, Et₃N, DMAP, CH₂Cl₂ (85–95%).

Scheme 3. Synthesis of baccatin III derivative 30

a. (i) LHMDS, THF, 0 °C, 4-pentenoyl chloride (78%); b. (i) HF.Py, THF (91%); (ii) CeCl₃, Ac₂O, THF (92%); (iii) Triethylsilyl chloride, imidazole, DMF (85%).

Scheme 4. Synthesis of britaxel derivative 32

a. LHMDS, THF, −40 °C b. (i) (PCy₃)₂(Cl₂)Ru=CHPh, DCM, room temp (ii) HF, Py, THF, 0 °C -room temp

Scheme 5

Synthesis of simplified taxol analog 39.