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Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues.
J Med Chem. 1998 Dec 31; 41(27):5410-9.JM

Abstract

Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 23c, d,f,g were found to have potent cytotoxic activity on A427 and PC-3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF7mdr cell lines, which overexpress a functionally active P-glycoprotein. Fluorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts. In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.

Authors+Show Affiliations

Institut Henri Beaufour, 5, avenue du Canada, F-91966 Les Ulis, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9876111

Citation

Lavergne, O, et al. "Homocamptothecins: Synthesis and Antitumor Activity of Novel E-ring-modified Camptothecin Analogues." Journal of Medicinal Chemistry, vol. 41, no. 27, 1998, pp. 5410-9.
Lavergne O, Lesueur-Ginot L, Pla Rodas F, et al. Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem. 1998;41(27):5410-9.
Lavergne, O., Lesueur-Ginot, L., Pla Rodas, F., Kasprzyk, P. G., Pommier, J., Demarquay, D., Prévost, G., Ulibarri, G., Rolland, A., Schiano-Liberatore, A. M., Harnett, J., Pons, D., Camara, J., & Bigg, D. C. (1998). Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. Journal of Medicinal Chemistry, 41(27), 5410-9.
Lavergne O, et al. Homocamptothecins: Synthesis and Antitumor Activity of Novel E-ring-modified Camptothecin Analogues. J Med Chem. 1998 Dec 31;41(27):5410-9. PubMed PMID: 9876111.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. AU - Lavergne,O, AU - Lesueur-Ginot,L, AU - Pla Rodas,F, AU - Kasprzyk,P G, AU - Pommier,J, AU - Demarquay,D, AU - Prévost,G, AU - Ulibarri,G, AU - Rolland,A, AU - Schiano-Liberatore,A M, AU - Harnett,J, AU - Pons,D, AU - Camara,J, AU - Bigg,D C, PY - 1999/1/6/pubmed PY - 1999/1/6/medline PY - 1999/1/6/entrez SP - 5410 EP - 9 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 41 IS - 27 N2 - Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 23c, d,f,g were found to have potent cytotoxic activity on A427 and PC-3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF7mdr cell lines, which overexpress a functionally active P-glycoprotein. Fluorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts. In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9876111/Homocamptothecins:_synthesis_and_antitumor_activity_of_novel_E_ring_modified_camptothecin_analogues_ L2 - https://dx.doi.org/10.1021/jm980400l DB - PRIME DP - Unbound Medicine ER -