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Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting viamaleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure–activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitroand in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.

COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones. Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure–activity relationships. SW480/Coti cells were found to overexpress ABCC1, and COTI-2 being a substrate for this efflux pump. This was unexpected, as ABCC1 has strong selectivity for glutathione adducts. The recognition by ABCC1 could be explained by the reduction kinetics of a ternary Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones.

Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [Ru^IIICl(6-n)(ind)n]^(3-n)- (n = 0−4; ind = indazole; counterions = Hind⁺ or Cl^-) and the compound trans-[Ru^IICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order:  [Ru^IIICl6]^3- < [Ru^IIICl4(ind)2]^- < [Ru^IIICl5(ind)]^2- ≪ [Ru^IIICl3(ind)3] < [Ru^IIICl2(ind)4]⁺ ≈ [Ru^IICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it.

Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [RuIIICl(6-n)(ind)n](3-n)-(n= 0−4; ind = indazole; counterions = Hind+or Cl-) and the compound trans-[RuIICl2(ind)4] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order:  [RuIIICl6]3-< [RuIIICl4(ind)2]-< [RuIIICl5(ind)]2-≪ [RuIIICl3(ind)3] < [RuIIICl2(ind)4]+≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it.

A series of osteotropic (bone-seeking) [(bis(phosphonomethyl)amino-κN)acetato-κO(2-)]platinum(II) complexes attached to diammine, ethane-1,2-diamine, cis-R,S-cyclohexane-1,2-diamine, trans-S,S-cyclohexane-1,2-diamine, or trans-R,R-cyclohexane-1,2-diamine has been synthesized in accord with the concept of drug targeting and characterized by elemental analysis, ¹H, ¹³C, and ³¹P NMR spectroscopy. The in vitro antitumor activity in ovarian cancer cells (CH1) has been determined by means of the MTT assay. In this cisplatin-sensitive cell line the complexes containing cyclohexane-1,2-diamine (chxn) displayed a high activity in comparison to the diammine and ethane-1,2-diamine counterparts. In agreement with structure−activity relationships of other chxn-containing platinum(II) complexes both [(bis(phosphonomethyl)amino-κN)acetato-κO(2-)](trans-cyclohexane-1,2-diamine)platinum(II) complexes show superior potency than the corresponding cis-congener whereas the trans-R,R isomer displays the highest activity. Within the series of complexes under investigation, potency decreases depending on the coordinated amine ligand in the following order:  trans-R,R-chxn > trans-S,S-chxn > NH3 ≥ cis-R,S-chxn > en.

A series of osteotropic (bone-seeking) [(bis(phosphonomethyl)amino-κN)acetato-κO(2-)]platinum(II) complexes attached to diammine, ethane-1,2-diamine, cis-R,S-cyclohexane-1,2-diamine, trans-S,S-cyclohexane-1,2-diamine, or trans-R,R-cyclohexane-1,2-diamine has been synthesized in accord with the concept of drug targeting and characterized by elemental analysis, 1H, 13C, and 31P NMR spectroscopy. The in vitro antitumor activity in ovarian cancer cells (CH1) has been determined by means of the MTT assay. In this cisplatin-sensitive cell line the complexes containing cyclohexane-1,2-diamine (chxn) displayed a high activity in comparison to the diammine and ethane-1,2-diamine counterparts. In agreement with structure−activity relationships of other chxn-containing platinum(II) complexes both [(bis(phosphonomethyl)amino-κN)acetato-κO(2-)](trans-cyclohexane-1,2-diamine)platinum(II) complexes show superior potency than the corresponding cis-congener whereas the trans-R,Risomer displays the highest activity. Within the series of complexes under investigation, potency decreases depending on the coordinated amine ligand in the following order:  trans-R,R-chxn > trans-S,S-chxn > NH3≥ cis-R,S-chxn > en.