title: Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity.
abstract: The synthesis, cytotoxicity, and nucleoside binding of some platinum-acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 ("PT-ACRAMTU"; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form) are reported. To establish structure-activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU x MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.
authors.affiliation: Department of Chemistry, Wake Forest University, P.O. Box 7486 Reynolda Station, Winston-Salem, NC 27109, USA.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Ackley
authors.forename: Colin G
authors.initials: CG
authors.lastname: Barry
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Mounce
authors.forename: Michael C
authors.initials: MC
authors.lastname: Farmer
authors.forename: Beth-Erin
authors.initials: BE
authors.lastname: Springer
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Day
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Wright
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Berners-Price
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hess
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea
chemical_list: D000970:Antineoplastic Agents; D009705:Nucleosides; D009944:Organoplatinum Compounds; D013890:Thiourea