Synthesis and evaluation of C-seco paclitaxel analogues

Tetrahedron Letters

Volumn 38, Issue 24, 1997, Pages 4273-4276

  Appendino, Giovanni ^a   Danieli, Bruno ^b   Jakupovic, Jasmin ^c   Belloro, Emanuela ^a   Scambia, Giovanni ^d   Bombardelli, Ezio ^e  

^a UNIVERSITY OF TURIN   (Italy)

^b CNR   (Italy)

^c TECHNISCHE UNIVERSITÄT BERLIN   (Germany)

^d CATHOLIC UNIVERSITY   (Italy)

^e INDENA S P A   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

DOCETAXEL; DOXORUBICIN; PACLITAXEL; TAXANE DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL LINE; CHIRALITY; CONTROLLED STUDY; DRUG RESISTANCE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IN VITRO STUDY; REACTION ANALYSIS; STEREOCHEMISTRY; TUMOR CELL;

EID: 0030968741     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)00877-0     Document Type: Article

References (25)

1. Part XXX in the series: The Chemistry and Occurrence of Taxane Derivatives. For part XXIX, see: Barboni, L.; Lambertucci, C.; Appendino, G.; Gabetta, B. Phytochemistry. 1997 (in press)
2. Chen, S.-H.; Farina, V. "Paclitaxel (Taxol®) Chemistry and Structure-Activity Relationships" in The Chemistry and Pharmacology of Taxol® and its Derivatives Farina, V. Ed.; Elsevier, 1995, pp. 165-253.
3. a) Bollag, D.M.; McQueney, P.A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C.M. Canc. Res. 1995, 55, 2325-2333.
4. b) Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569.
5. ter Haar, E.; Kowalski, R.J.; Hamel, E.; Lin, C.M.; Longley, R.E.; Gunasekera, S.P.; Rosenkranz, H.S.; Day, B.W. Biochemistry 1996, 35, 243-250.
6. a) Winkler, J.D.; Axelsen, P.H. Bioorg. Med. Chem. Lett. 1996, 6, 2963-2966.
7. b) ter Haar, Rosenkranz, H.S.; Hamel, E.; Day, B.W. Bioorg. Med Chem. 1996, 4, 1659-1671.
8. Compared to paclitaxel, 10-deacetylpaclitaxel is more than 20 times less cytotoxic on KB cells (McLaughlin, J.L.; Miller, R.W.; Powell, R.G.; Smith Jr., C.R. J. Nat. Prod. 1981, 44, 312-319), and ca 3 times less cytotoxic on J777.2 cells (Kingston, D.G.I.; Samaranayake, G.; Ivey, C.A. J. Nat. Prod. 1995, 53, 1-12). Deacetylation at C-10 caused a decreased cytotoxicity also in taxoids of the 3'-dephenyl-3'-alkyl type (Ojima, I.; Slater, J.C.; Michaud, E.; Kuduk, S.C.; Bounaud, P.-Y.; Vrignaud, P.; Bissery, M.-C.; Veith, J.M.; Pera, P.; Bernacki, R.J. J. Med. Chem. 1996, 39, 3889-3896). Interestingly, paclitaxel and 10-deacetylpaclitaxel have instead a similar affinity for tubulin (Guéritte-Voegelein, F.; Guénard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, P. J. Med. Chem 1991, 34, 992-998).
9. Compared to paclitaxel, 10-deacetylpaclitaxel is more than 20 times less cytotoxic on KB cells (McLaughlin, J.L.; Miller, R.W.; Powell, R.G.; Smith Jr., C.R. J. Nat. Prod. 1981, 44, 312-319), and ca 3 times less cytotoxic on J777.2 cells (Kingston, D.G.I.; Samaranayake, G.; Ivey, C.A. J. Nat. Prod. 1995, 53, 1-12). Deacetylation at C-10 caused a decreased cytotoxicity also in taxoids of the 3'-dephenyl-3'-alkyl type (Ojima, I.; Slater, J.C.; Michaud, E.; Kuduk, S.C.; Bounaud, P.-Y.; Vrignaud, P.; Bissery, M.-C.; Veith, J.M.; Pera, P.; Bernacki, R.J. J. Med. Chem. 1996, 39, 3889-3896). Interestingly, paclitaxel and 10-deacetylpaclitaxel have instead a similar affinity for tubulin (Guéritte-Voegelein, F.; Guénard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, P. J. Med. Chem 1991, 34, 992-998).
10. Compared to paclitaxel, 10-deacetylpaclitaxel is more than 20 times less cytotoxic on KB cells (McLaughlin, J.L.; Miller, R.W.; Powell, R.G.; Smith Jr., C.R. J. Nat. Prod. 1981, 44, 312-319), and ca 3 times less cytotoxic on J777.2 cells (Kingston, D.G.I.; Samaranayake, G.; Ivey, C.A. J. Nat. Prod. 1995, 53, 1-12). Deacetylation at C-10 caused a decreased cytotoxicity also in taxoids of the 3'-dephenyl-3'-alkyl type (Ojima, I.; Slater, J.C.; Michaud, E.; Kuduk, S.C.; Bounaud, P.-Y.; Vrignaud, P.; Bissery, M.-C.; Veith, J.M.; Pera, P.; Bernacki, R.J. J. Med. Chem. 1996, 39, 3889-3896). Interestingly, paclitaxel and 10-deacetylpaclitaxel have instead a similar affinity for tubulin (Guéritte-Voegelein, F.; Guénard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, P. J. Med. Chem 1991, 34, 992-998).
11. Compared to paclitaxel, 10-deacetylpaclitaxel is more than 20 times less cytotoxic on KB cells (McLaughlin, J.L.; Miller, R.W.; Powell, R.G.; Smith Jr., C.R. J. Nat. Prod. 1981, 44, 312-319), and ca 3 times less cytotoxic on J777.2 cells (Kingston, D.G.I.; Samaranayake, G.; Ivey, C.A. J. Nat. Prod. 1995, 53, 1-12). Deacetylation at C-10 caused a decreased cytotoxicity also in taxoids of the 3'-dephenyl-3'-alkyl type (Ojima, I.; Slater, J.C.; Michaud, E.; Kuduk, S.C.; Bounaud, P.-Y.; Vrignaud, P.; Bissery, M.-C.; Veith, J.M.; Pera, P.; Bernacki, R.J. J. Med. Chem. 1996, 39, 3889-3896). Interestingly, paclitaxel and 10-deacetylpaclitaxel have instead a similar affinity for tubulin (Guéritte-Voegelein, F.; Guénard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, P. J. Med. Chem 1991, 34, 992-998).
12. Appendino, G.; Jakupovic, J.; Cravotto, G.; Enriù, R.; Varese, M.; Bombardelli, E. Tetrahedron Lett. 1995, 3233-3236.
13. 2) and solvents (EtOH, i-propanol).
14. Denis, J.-N.; Greene, A.E.; Guénard, D.; Guéritte-Voegelein, F.; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917-5919.
15. 4) and evaporation, the residue was purified by CC (20 g silica gel) with a hexane-EtOAc gradient (9:1 → 8:2) to give, in order of elution, 132 mg (15%) of the 7,9,13-triTES derivative, 500 mg (65%) of the 7.9-diTES derivative (4b), 22 mg (5%) of the 7-TES derivative and 18 mg (4%) of the 9-TES derivative.
16. Johnson, R.A.; Nidy, E.G.; Dobrowolski, P.J.; Gebhard, I.; Qualls, S.J.; Wicnienski, N.A.; Kelly, R.C. Tetrahedron Lett. 1994, 7893-7896.
17. 3, 60 °C): δ 8.08 (AA', o-Bz), 7.58 (C, p-Bz), 7.48 (BB', m-Bz), 7.43 (C, p-Ph), 7.41 (A,A' -o-Ph), 7.37 (B,B' m-Ph), 7.12 (d, J=9.5 Hz, NH), 6.45 (br s, 9-OH), 6.23 (ddq, J=10.0, 7.0, 1.5 Hz, H-13), 5.90 (dd, J=10.0, 3.0 Hz, H-3'), 5.63 (br d, J=9.0 Hz, H-2), 5.22 (br d, J=11.5 Hz, H-5), 5.18 (br d, J=8.0, H-20a), 4.82 (d, J=3.0 Hz, H-2'), 4.30 (br d, J=9.0 Hz, H-3), 4.29 (br d, J=8.0 Hz, H-20b), 3.89 (br ddd, J=11.0, 6.0, 6.0 Hz, H-7a), 3.72 (br ddd, J=11.0, 6.5, 6.0 Hz, H-7b), 2.85 (br dd, J=16.0, 7.0 Hz, H-14a), 2.59 (br m, H-6a), 2.39 (br dd, J=16.0, 10.0 Hz, H-14b), 2.10 (m, H-6b), 1.91 (br s, OAc), 1.89 (br s, H-19), 1.81 (d, J=1.5 Hz, H-18), 1.26 (s, H-17), 1.11 (s, H-16).
18. 3, 60°C): δ 8.05 (AA', o-Bz), 7.60 (C, p-Bz), 7.48 (BB', m-Bz), 7.41 (A,A'-o-Ph), 7.37 (B,B', m-Ph), 7.29 (C, p-Ph), 6.45 (s, 9-OH), 6.23 (ddq, J=10.0, 7.0, 1.5 Hz, H-13), 5.64 (br d, J=9.0 Hz, H-2), 5.49 (d, J=9.5 Hz, NH), 5.32 (dd, J=10.0, 3.0 Hz, H-3'), 5.26 (br d, J=11.5 Hz, H-5), 5.16 (d, J=8.0, H-20a), 4.67 (d, J=3.0 Hz, H-2'), 4.35 (br d, J=9.0 Hz, H-3), 4.29 (d, J=8.0 Hz, H-20b), 3.86 (ddd, J=11.0, 6.0, 6.0 Hz, H-7a), 3.70 (ddd, J=11.0, 6.5, 6.5 Hz, H-7b), 2.80 (br dd, J=16.0, 7.0 Hz, H-14a), 2.52 (m, H-6a), 2.44 (br dd, J=16.0, 10.0 Hz, H-14b), 2.18 (s, 1-OH), 2.10 (m, H-6b), 1.93 (s, OAc), 1.86 (brs, H-19), 1.85 (d, J=1.5 Hz, H-18), 1.31 (s, BOC), 1.28 (s, H-17), 1.12 (s, H-16).
19. a) Liang, X.; Kingston, D.G.I.; Long, B.H.; Fairchild, C.A.; Johnston, K.A. Tetrahedron Lett. 1995, 7795-7798.
20. b) Bouchard, H.; Pulicani, J.-P.; Vuilhorgne, M.; Bourzat, J.-D.; Commerçon, A. Tetrahedron Lett. 1994, 9713-9716.
21. 2, MeOH, 24 h, 54% 7β-epimer, 23% 7α-epimer).
22. 3): δ 191.1 (s, C-10), 173.3 (s, C-1'), 169.0 (s, 4-OAc), 167.4 (s, Bz), 155.8 (s, BOC), 148.8 (s, C-9), 142.1 (s, C-11), 136.8 (s, C-12), 133.8 (d, p-Bz), 129.7 (d, m-Bz), 129.3 (i-Bz), 128.9 (d, o-Bz), 124 4 (s, C-8), 87.2 (d, C-5), 86.1 (s, C-4), 80.3 (s, C-1), 79.9 (s, BOC), 74.8 (d, C-2), 74.8 (t, C-20), 73.4 (d, C-2'), 70.5 (d, C-13), 59.7 (t, C-7), 51.4 (d, C-3'), 44.4 (d, C-3), 42.9 (s, C-15), 40.8 (t, C-4'), 37.5 (t, C-6), 36.5 (t, C-14), 28.1 (q, BOC), 24.9 (d, C-5'), 24.7 (q, C-17), 23.1 (q, C-6'), 22.1 (q, C-7'), 22.1 (q, 4-OAc), 21.2 (q, C-16), 14.8 (q, C-18), 14.4 (q, C-19).
23. 3, 60 °C): δ 8 09 (AA', o-Bz), 7.59 (C, p-Bz), 7.48 (BB', m-Bz), 6.42 (br s, 9-OH), 6.22 (ddq, J=9.0, 7.0, 1.5 Hz, H-13), 5.99 (d, J=9.5 Hz, NH), 5.63 (br d, J=9.0 Hz, H-2), 5.22 (br d, J=111.5 Hz, H-5), 5.15 (br d, J=8.0, H-20a), 4.54 (dddd, J=9.5, 9.5, 5.5, 3.0 Hz, H-3'), 4.33 (br d, J=9.0 Hz, H-3), 4.30 (br d, J=8.0 Hz, H-20b), 4.29 (d, J=3.0 Hz, H-2'), 3.89 (br ddd, J=11.0, 6.0, 6.0 Hz, H-7a), 3.70 (br ddd, J=11.0, 7.0, 6.0 Hz, H-7b), 2.82 (br dd, J=16.0, 7.0 Hz, H-14a), 2.52 (br m, H-6a), 2.15 (br s, 1-OH), 2.06 (br m, H-6b), 2.43 (br dd, J=16.0, 9.0 Hz, H-14b), 2.09 (t, J=8.0 Hz, 2-Hex), 1.93 (br s, OAc), 1.90 (br s, H-19), 1.89 (d, J=1.5 Hz, H-18), 1.61 (ddd, J=14.0, 9.5, 5.5 Hz, H-4'a), 1.51 (m, H-4'b), 1.51 (m, 3-Hex), 1.70 (m, H-5'), 1.28 (s, H-17), 1.22 (m, 4-Hex and 5-Hex), 1.13 (s, H-16), 1.00 (d, J=6.0 Hz, H-6',H-7'), 0.83 (t, J=6.5Hz, 6-Hex).
24. Ojima, I.; Duclos, O.; Kuduk, S.D.; Sun C.-M.; Slater, J.C.; Lavelle, F.; Veith, J.M.; Bernacki, R.J. Bioorg. Med. Chem. Lett. 1994, 4, 2631-2634.
25. 501c in the tubulin assembly assay was 1.8.