relation: http://d-scholarship-dev.library.pitt.edu/20617/
title: The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity
creator: Bom, D
creator: Curran, DP
creator: Kruszewski, S
creator: Zimmer, SG
creator: Strode, JT
creator: Kohlhagen, G
creator: Du, W
creator: Chavan, AJ
creator: Fraley, KA
creator: Bingcang, AL
creator: Latus, LJ
creator: Pommier, Y
creator: Burke, TG
description: We describe the rational design and synthesis of B- and A,B-ring-modified camptothecins. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t( 1/2 ) of 130 rain and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.
date: 2000-10-19
type: Article
type: PeerReviewed
format: text/plain
language: en
rights: attached
identifier: http://d-scholarship-dev.library.pitt.edu/20617/1/licence.txt
identifier:   Bom, D and Curran, DP and Kruszewski, S and Zimmer, SG and Strode, JT and Kohlhagen, G and Du, W and Chavan, AJ and Fraley, KA and Bingcang, AL and Latus, LJ and Pommier, Y and Burke, TG  (2000) The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.  Journal of Medicinal Chemistry, 43 (21).  3970 - 3980.  ISSN 0022-2623     
relation: 10.1021/jm000144o