title: Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity.
abstract: Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
authors.forename: W D
authors.initials: WD
authors.lastname: Kingsbury
authors.forename: J C
authors.initials: JC
authors.lastname: Boehm
authors.forename: D R
authors.initials: DR
authors.lastname: Jakas
authors.forename: K G
authors.initials: KG
authors.lastname: Holden
authors.forename: S M
authors.initials: SM
authors.lastname: Hecht
authors.forename: G
authors.initials: G
authors.lastname: Gallagher
authors.forename: M J
authors.initials: MJ
authors.lastname: Caranfa
authors.forename: F L
authors.initials: FL
authors.lastname: McCabe
authors.forename: L F
authors.initials: LF
authors.lastname: Faucette
authors.forename: R K
authors.initials: RK
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002417:Cattle; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy; D004278:DNA, Superhelical / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D010957:Plasmids; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D007202:Indicators and Reagents; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin