Synthesis, biological activity, and DNA-damage profile of platinum-threading intercalator conjugates designed to target adenine.
PT-ACRAMTU {[PtCl(en)(ACRAMTU)](NO3)2, 2; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, 1, en = ethane-1,2-diamine} is the prototype of a series of DNA-targeted adenine-affinic dual intercalating/platinating agents. Several novel 4,9-disubstituted acridines and the corresponding platinum-acridine conjugates were synthesized. The newly introduced 4-carboxamide side chains contain H-bond donor/acceptor functions designed to promote groove- and sequence-specific platinum binding. In HL-60 (leukemia) and H460 (lung) cancer cells, IC50 values in the micromolar to millimolar range were observed. Several of the intercalators show enhanced cytotoxicity compared to prototype 1, but conjugate 2 appears to be the most potent hybrid agent. Enzymatic digestion assays in conjunction with liquid chromatography-electrospray mass spectrometry analysis indicate that the new conjugates produce PT-ACRAMTU-type DNA damage. Platinum-modified 2'-deoxyguanosine, dG, and several dinucleotide fragments, d(NpN)*, were detected. One of the conjugates showed significantly higher levels of binding to A-containing sites than conjugate 2 (35 +/- 3% vs 24 +/- 3%). Possible structure-activity relationships are discussed.
Guddneppanavar
Rajsekhar
R
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
Saluta
Gilda
G
Kucera
Gregory L
GL
Bierbach
Ulrich
U
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000225:Adenine / Q000737:chemistry*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry
C471910:1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea; D000166:Acridines; D018736:DNA Adducts; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D014508:Urea; D004247:DNA; C427203:calf thymus DNA; D000225:Adenine