Novel approaches to polynuclear platinum pro-drugs. Selective release of cytotoxic platinum-spermidine species through hydrolytic cleavage of carbamates.
BBR3464 is a novel trinuclear platinum drug currently in Phase II clinical trials. Polyamine-bridged dinuclear platinum compounds as represented by [[trans-Pt(NH(3))(2)Cl](2)-mu-spermidine-N(1),N(8)]Cl(3) (1) are highly interesting second-generation analogues of BBR3464 because the hydrogen-bonding and electrostatic contributions of the central platinum-amine group in BBR3464 are replicated by the free, noncoordinated "central" quaternary nitrogens of the linear polyamine linker while the presence of two separate Pt-Cl bonds maintains the bifunctional binding mode on the DNA adducts. Preclinical investigations confirm the potency of these species with cytotoxicity in the nanomolar range. This remarkable potency results in a relatively narrow therapeutic index. To enhance the therapeutic index of these drugs, we investigated the potential for "pro-drug" delivery of less toxic and better tolerated derivatives such as the compounds [[trans-Pt(NH(3))(2)Cl](2)-mu-N(4)-R-spermidine-N(1),N(8)]Cl(2) where N(4)-R represents BOC (tert-butyl), CBz (benzyl), and Fmoc (fluorenylmethyl) carbamate blocking groups, 2-4, respectively. The bulky Fmoc derivative showed evidence for conformational isomers by (1)H NMR spectroscopy due to the inequivalence of the two n-propyl and n-butyl side chains of the spermidine moiety. The rate constants for hydrolysis and release of 1 were calculated. Release of cytotoxic 1 at physiologically relevant pH followed the order 4 > 2 > 3. The calculated values for 4 (pH 5, 6.0(+/-3.9) x 10(-10) s(-1); pH 6, 6.5(+/-0.2) x 10(-9) s(-1); pH 7, 6.0(+/-0.2) x 10(-8) s(-1); pH 8, 1.6(+/-0.1) x 10(-7) s(-1)) show a more pronounced pH dependence compared to 2 (pH 5, 4.6(+/-0.1) x 10(-8) s(-1); pH 6, 4.2(+/-0.1) x 10(-8) s(-1); pH 7, 3.2(+/-0.1) x 10(-8) s(-1)). Preliminary biological assays of cellular uptake and cytotoxicity confirm the utility of the pro-drug concept. While blocked-polyamine compounds such as 2-4 are, in general, 2-3 orders of magnitude less cytotoxic than 1, there is significant cell type variability. Specifically, the Fmoc derivative 4 showed significantly enhanced cytotoxicity warranting further study of the pro-drug concept for greater selectivity and/or oral delivery.
Hegmans
A
A
Department of Chemistry and Internal Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23284-2006, USA.
Qu
Y
Y
Kelland
L R
LR
Roberts
J D
JD
Farrell
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210; D051379:Mice; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010051:Ovarian Neoplasms; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013095:Spermidine / Q000737:chemistry* / Q000494:pharmacology; D013096:Spermine / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002219:Carbamates; D009944:Organoplatinum Compounds; D011073:Polyamines; D011355:Prodrugs; D013096:Spermine; C114062:BBR 3464; D013095:Spermidine