Water soluble palladium() and platinum() acyclic diaminocarbene complexes: solution behavior, DNA binding, and antiproliferative activity

• Published in: New journal of chemistry 2020-04, Vol.44 (15), p.5762-5773
• Main Authors: Serebryanskaya, Tatiyana V, Kinzhalov, Mikhail A, Bakulev, Vladimir, Alekseev, Georgii, Andreeva, Anastasiya, Gushchin, Pavel V, Protas, Aleksandra V, Smirnov, Andrey S, Panikorovskii, Taras L, Lippmann, Petra, Ott, Ingo, Verbilo, Cyril M, Zuraev, Alexander V, Bunev, Alexander S, Boyarskiy, Vadim P, Kasyanenko, Nina A
• Format: Article
• Language: English
• Subjects: Absorption spectra; Adducts; Antiproliferatives; Aqueous solutions; Binding; Biotechnology; Birefringence; Computed tomography; Crystal structure; Crystallography; Deoxyribonucleic acid; Dichroism; DNA; Fluorescence; Grooves; Mass spectra; Mass spectrometry; NMR spectroscopy; Palladium; Platinum; Single crystals; Viscometry; X-ray diffraction
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d0nj00060d

Bis-ADC complexes cis -[Pd{C(NHC 6 H 4 NH 2 )N(H)R} 2 ]Cl 2 (R = Xyl 4a , Cy 4b , C 6 H 4 -4-F 4c ) and cis -[Pt{C(NHC 6 H 4 NH 2 )N(H)R} 2 ]Cl 2 (R = Xyl 5a , Cy 5b , C 6 H 4 -4-F 5c ) were synthesized via the metal-mediated coupling of two isocyanide ligands in cis -[MCl 2 (CNR) 2 ] (M = Pd, Pt; R = Xyl, Cy, C 6 H 4 -4-F) and 1,2-diaminobenzene. New compounds 4c and 5a-c were characterized by HR ESI + -MS, IR, and 1 H, 13 C{ 1 H} and 195 Pt{ 1 H} NMR spectroscopy; the structures of 4a and 5a were elucidated by single-crystal X-ray diffraction. The stability of the ADC complexes in aqueous media (5 mM NaCl) was monitored by UV absorption spectroscopy, HR ESI + mass spectrometry, and 195 Pt{ 1 H} NMR spectroscopy (for 5a ). Molar conductivity measurements in MeOH (Λ M = 167-173 Ω −1 mol −1 cm 2 ) indicate that, in this solvent, the ADC complexes exist as dicationic species of [A][Q] 2 type. The ADC complexes binding to CT DNA was investigated by means of spectroscopic and hydrodynamic techniques including UV absorption and circular dichroism spectroscopy, fluorescence spectroscopy, low-gradient viscometry, flow birefringence, and AFM imaging. As a result, complexes 4a and 5a were shown to bind double-stranded DNA predominantly via the formation of monofunctional adducts in the major groove of the macromolecule. Binding of the ADC complexes also provokes the formation of a large number of intermolecular DNA-DNA contacts in solution. The antiproliferative activity of all prepared ADC complexes 4a-c and 5a-c was evaluated in vitro against three human carcinoma cell lines (HT-29, MDA-MB-231, and MCF-7) and two non-tumorigenic cell lines (L929 and RC-124) and compared to that of cisplatin. Among the compounds studied, complexes 4a and 5a appeared to be the most active species with IC 50 values in MCF-7 cells of about 10 μM. Water soluble Pd( ii ) and Pt( ii )-ADC species synthesized via the metal-mediated coupling of isocyanides and 1,2-diaminobenzene have demonstrated antitumor potential.