title: 14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.
abstract: 14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
authors.affiliation: Threshold Pharmaceuticals , 1300 Seaport Blvd, Suite 500, Redwood City, California 94063, United States. jduan@thresholdpharm.com
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cai
authors.forename: Fanying
authors.initials: F
authors.lastname: Meng
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Sun
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Donald
authors.initials: D
authors.lastname: Jung
authors.forename: Hailong
authors.initials: H
authors.lastname: Jiao
authors.forename: Jackson
authors.initials: J
authors.lastname: Matteucci
authors.forename: Brian
authors.initials: B
authors.lastname: Jung
authors.forename: Deepthi
authors.initials: D
authors.lastname: Bhupathi
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Ahluwalia
authors.forename: Heli
authors.initials: H
authors.lastname: Huang
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.forename: Mark
authors.initials: M
authors.lastname: Matteucci
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002166:Camptothecin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C558738:7-ethyl-14-aminocamptothecin; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1