Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile

Abstract

Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (bis-capronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development.

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

“…22 Kinetic studies of substitution of BBR3610 by small molecules such as methionine and 5′-GMP, 20 also suggest a broadly similar profile in aqueous medium to that of BBR3464, with likelihood of similar degradation (metabolism) profiles for polyamine-bridged species in comparison to that of the trinuclear drug. 12,20 The use of less substitution-labile leaving groups 21 or use of different geometries (1,1/ c,c ) by use of 1,2-dach carrier groups 22,40 are valid approaches to systematically alter the pharmacokinetic profile of the PPCs.…”

Coordination compounds in cancer: Past, present and perspectives

“…Among these compounds, dinuclear platinum complex CT-47463 (Fig. 7c) possesses a cytotoxic activity against cisplatin-resistant ovarian and squamous cell carcinoma, and osteosarcoma human cell lines with IC 50 (i.e., drug concentration required for 50% inhibition of cell growth) of 0.003, 0.77 and 0.041 mM (Gatti et al, 2009). The CT-47463 inhibits tumour growth in platinum-resistant human ovarian carcinoma xenograft by 80% (Barry and Sadler, 2013).…”

Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

“…Replacement of the chloride leaving groups in BBR3610 with butyrate or capronate alkylcarboxylates (CT-47518 and CT-47463 respectively, Fig. 1C), improved pharmacokinetic and pharmacodynamic profiles of the parent drug [14]. These compounds were found to overcome resistance due to defects in DNA mismatch repair and were highly effective in cisplatin- and oxaliplatin-resistant cell lines.…”