Terpene conjugates of diaminedichloridoplatinum(II) complexes: antiproliferative effects in HL-60 leukemia, 518A2 melanoma, and HT-29 colon cancer cells.
Twenty-eight [6-(aminomethyl)nicotinate]dichloridoplatinum(II) complexes 1 esterified with various terpene alcohols either directly or via alkyl spacers were tested for antiproliferative activity in human 518A2 melanoma and HL-60 leukemia cells. Generally, conjugates with menthanes and polycyclic sesquiterpenes attached via propane-1,2-diyl spacers were most active. In the melanoma cells, the propane-1,2-diyl-spacered conjugates of (-)-menthol (1a(2')), (+)-neomenthol (1b(2')), (-)-carvomenthol (1h(2')), and (-)-isolongifolol (1n(2')) displayed growth inhibition at IC(50)<4 microM which is ten times smaller than that of cisplatin. The stationary diamino ligand was also crucial. The (-)-menthyl ester complexes with 2,3-diaminopropanoate (9a) and 2,4-diaminobutanoate (10a) ligands caused a greater and persistent growth inhibition in HT-29 colon cancer cells upon long-term exposure when compared to the 6-(aminomethyl)nicotinate analogue 1a. The cedrenyl ester 1l and the menthoxyisopropyl ester 1a(2') proved most efficacious in all three tumor cell lines. The DNA binding of complexes 1 was assessed by electrophoretic band-shift experiments and found correlated to the terpene structure but not to the observed antiproliferative activities.
Bernhardt
Günther
G
Institut für Pharmazie der Universität Regensburg, D-93053 Regensburg.
Biersack
Bernhard
B
Organisch-chemisches Laboratorium der Universität Bayreuth, Universitätsstrasse 30, NW 1, D-95447 Bayreuth (fax: +49 (0)921 552671).
Bollwein
Susanne
S
Institut für Pharmazie der Universität Regensburg, D-93053 Regensburg.
Schobert
Rainer
R
Organisch-chemisches Laboratorium der Universität Bayreuth, Universitätsstrasse 30, NW 1, D-95447 Bayreuth (fax: +49 (0)921 552671).
Zoldakova
Miroslava
M
Organisch-chemisches Laboratorium der Universität Bayreuth, Universitätsstrasse 30, NW 1, D-95447 Bayreuth (fax: +49 (0)921 552671).
D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008545:Melanoma / Q000473:pathology*; D008968:Molecular Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012015:Reference Standards; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D009944:Organoplatinum Compounds; D013729:Terpenes