Automated Parallel Solid-Phase Synthesis and Anticancer Screening of a Library of Peptide-Tethered Platinum(II) Complexes

Abstract

The automated parallel solid-phase synthesis of a 36-member library of peptide-tethered platinum(II) complexes is described. The identity and quality of each product were confirmed by mass spectrometry and (1)H NMR. Subsequently, each compound was screened for in vitro anticancer activity by treating the A2780 (human ovarian carcinoma) cell line with two concentrations of the drugs (100 and 10 microM) in quadruplicate. The reduction of cell proliferation induced by the drugs at these concentrations was determined with the MTT colorimetric assay (MTT = 3-(4',5'-dimethylthiazol-2'-yl)-2,5-diphenyltetrazolium bromide) and compared to cisplatin. Even though no very active library members could be identified, five apparently most active (8[1], 8[4], 8[10], 8[13], and 8[24]) and two inactive complexes (8[33] and 8[34]) were purified using gel permeation chromatography and fully characterized by NMR spectroscopy ((1)H, (195)Pt) and MS. The IC(50) values of these complexes and cisplatin in A2780 cells were subsequently determined using the MTT assay in a conventional manner. All seven complexes have an IC(50) above 100 microM, confirming the results generated by the assay at 100 and 10 microM of the crude reaction products.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

“…This technology was used to screen dozens of platinum(II)-peptide conjugates in vitro for anticancer activity, although no significant hits were obtained in this screen. 174 Although these peptide conjugates exhibit a reduced capacity to platinate DNA, and consequently reduced potency, the DNA sequence specificity of platination is generally unaltered with different peptide sequences. 175 We note briefly, however, that use of individual charged amino acids, such as ornithine, lysine, or arginine, in place of the nonleaving group ligands can alter this specificity.…”

Combinatorial discovery of new asymmetric platinum anticancer complexes is made possible with solid-phase synthetic methods

“…3). Remarkably in other combinatorial evaluations of platinum antitumour drugs far fewer active compounds were discovered [20,21], illustrating the high potential of asymmetric cisplatin analogues.…”

Solid‐Phase Synthesis of Transition‐Metal Complexes

“…Platinum(II) complexes with aliphatic amines as ligands (24, Scheme 13) reported by Reedijk et al are reasonably stable under acidic conditions and libraries of peptide-platinum(II) conjugates were prepared on solid phase (using a Rink amide linker [6] ) and their anticancer activity was evaluated after cleavage from the support. [25] For resinbound Pt II complexes, gel-phase 195 Pt NMR spectroscopy was found to be a very useful analytical tool for monitoring the reaction. [23] The use of 22-PS or 24-PS as starting materials for the SPS of oligonuclear metal complexes with welldefined chain lengths and end groups awaits exploration.…”

“…The pepti- de99m Tc-chelate conjugate 8-PS has been prepared by SPPS as a potential radiopharmaceutical equipped with a targeting vector (Scheme 5). [21] Reedijk et al reported the first example of a solid-phase synthesis of peptide-tethered dichloroplatinum(II) complexes, [22][23][24] and the automated synthesis of a family of 36 analogues [25] as well as the SPPS of dinuclear lysine-bridged platinum(II) complexes (Scheme 5; 9-PS) [26] with the aim to discover new potent platinum anticancer agents. DNA-sequence selective hairpin polyamide platinum(II) complexes have also been prepared on solid supports.…”

“…[40] Often metalation is the last step in the SPS so that the benefits of using solid-phase methodology are not immediately clear, as in this case metalation could also easily be performed after cleavage of the molecule from the solid support in homogeneous solution (on-resin labelling vs. post-SPS labelling). However, when combinatorial chemistry comes into play (e.g., solid-phase library synthesis [25] and solid-phase library screening [41] ) the necessity of introducing the metal while the molecule is still bound to the support becomes evident. This is even mandatory when the transition metal constitutes an integral part of an oligomer backbone (Scheme 6).…”