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.

Ion mobility and Top-down MS complementary approaches for the structural analysis of protein models bound to anticancer metallodrugs

“…In addition, many tumor cells display intrinsic or acquired resistance to platinum (Pt)-based drugs, thus further limiting their use [6][7][8]. Hence, intensive efforts have been channeled towards the discovery of alternative Pt-based anticancer agents [9,10]. Of the several thousand Pt compounds synthesized, only about 35 have entered clinical trials [11][12][13].…”

Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation

“…The goal of replacing PEt 3 in compound 1 with bulkier phosphine ligands was to enhance the metal's selectivity (and potentially tolerability) by reducing its chemical reactivity. As ligands trans to phosphine, eight thioureas containing N-heterocyclic chromophores of varying basicity, borrowed from our extensive library of ACRAMTU derivatives, were introduced: 9-aminoacridines L1, L2, L5 (pK a ≈ 9−10, DNA intercalating), 15,16 1,2,3,4-tetrahydro-9-aminoacridine (tacrin) L3 and -4-aminoquinoline L4 (pK a ≈ 9−10, nonintercalating), 17,18 9-aminoacridine-4-carboxamides L6 and L7 (pK a ≈ 8), 19 and 9-substituted L8 (pK a ≈ 4, nonintercalating). 20 In addition, the simple derivative 1,1,3,3-tetramethylthiourea (tmtu, L9) was also studied.…”

Guanine binding of a cytotoxic platinum–acridin-9-ylthiourea conjugate monitored by 1-D 1H and 2-D [1H,15N] NMR spectroscopy: Hydrolysis is not the rate-determining step

“…While the structure of this adduct and its impact on DNA conformation have been studied in detail both in DNA and oligonucleotide/nucleoside models, the mechanism of its formation remains to be explored. In a recent structure-activity relationship (SAR) study [10], we demonstrated using model reactions between 1 and 2 0 -deoxyguanosine (dG) that the monofunctional adduct, [Pt(en)(ACRAMTU-S)(dG-N7)] 3+ (dG * ) forms at a significantly slower rate than adducts of classical platinum am(m)ines under similar conditions. A half-life of adduct formation of 7.5 h was determined from timedependent NMR spectra when 1 mM Pt was incubated with 3 mM of dG at 37°C [10].…”

“…In a recent structure-activity relationship (SAR) study [10], we demonstrated using model reactions between 1 and 2 0 -deoxyguanosine (dG) that the monofunctional adduct, [Pt(en)(ACRAMTU-S)(dG-N7)] 3+ (dG * ) forms at a significantly slower rate than adducts of classical platinum am(m)ines under similar conditions. A half-life of adduct formation of 7.5 h was determined from timedependent NMR spectra when 1 mM Pt was incubated with 3 mM of dG at 37°C [10]. In contrast, reactions of conjugate 1 with calf thymus DNA proceed significantly faster and are virtually complete after 12 h [6].…”