title: Structure-activity relationship of alkyl 9-nitrocamptothecin esters.
abstract: OBJECTIVE
  To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters.
  
  
  METHODS
  Two alkyl 9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhydride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against human leukemia cell lines HL-60 and U-937. Flow cytometry analysis was used to identify the cell cycle phase targeted by the esters and quantify the extent of ester-induced cell death (apoptosis).
  
  
  RESULTS
  Esters 5b and 5c demonstrated great abilities to inhibit growth of the leukemia cells followed by induction of apoptosis; esters 5a, 5e, and 5g induced slight perturbations in the cell cycle at high concentrations; and esters 5d, 5f, and 5h were completely inactive against the cell lines tested. Thus these esters showed the cell anti-proliferative activity in an order of 5b approximately 5c>5a approximately 5e approximately 5g>5d approximately 5f approximately 5h. Esters 5b, 5c, and 5e were tested in vivo against various human carcinomas in nude mice grown as xenografts. Only 5b and 5c showed a significant antitumor activity. Particularly, ester 5b demonstrated an antitumor activity against a broad spectrum of human carcinomas including breast, lung, colon, pancreas, stomach, ovarian, and melanoma, etc.
  
  
  CONCLUSIONS
  These esters act like prodrugs of their parental 9-nitrocamptothecin. High drug doses need to be administered to animals in order to inhibit growth, and induce regression, of human tumor xenografts in nude mice. These compounds may be developed into potent anticancer drugs due to their low toxicity.
authors.affiliation: The Stehlin Foundation for Cancer Research at St. Joseph Hospital, 1918 Chenevert, Houston, Texas 77003, USA. zcao@stehlin.org
authors.forename: Zhi-Song
authors.initials: ZS
authors.lastname: Cao
authors.forename: Panayotis
authors.initials: P
authors.lastname: Pantazis
authors.forename: John
authors.initials: J
authors.lastname: Mendoza
authors.forename: Janet
authors.initials: J
authors.lastname: Early
authors.forename: Anthony
authors.initials: A
authors.lastname: Kozielski
authors.forename: Nick
authors.initials: N
authors.lastname: Harris
authors.forename: Beppino
authors.initials: B
authors.lastname: Giovanella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D011355:Prodrugs; C079905:rubitecan; D002166:Camptothecin