Palladium(II) and Platinum(II) Deprotonated Diaminocarbene Complexes Based on N-(2-Pyridyl)ureas with Oxadiazole Periphery

Metal mediated coupling of isocyanides with substituted N-(pyridine-2-yl) ureas was first used to incorporate privileged biological motifs into platinum metal complexes. We synthesized two palladium(II) and two platinum(II) cyclometallated species with oxadiazole cores. The compounds were isolated in good yields (61–73%) and characterized by high-resolution mass spectrometry and 1H, 13C, and 195Pt NMR spectroscopies. The structures of three complexes were additionally elucidated by X-ray diffraction analysis. These complexes indeed showed cytotoxic activity. The species bearing the 1,3,4-oxadiazole moiety exhibit more potency than the ones with the 1,2,4-oxadiazole ring. Particularly, the cytotoxic effect of both 1,3,4-oxadiazole-based complexes towards T98G cells significantly exceeds the common antitumor metal-drug cisplatin.

[1]  V. Boyarskiy,et al.  Reaction of Coordinated Isocyanides with Substituted N-(2-Pyridyl)Ureas as a Route to New Cyclometallated Pd(Ii) Complexes , 2022, SSRN Electronic Journal.

[2]  V. Khedkar,et al.  Oxadiazole: A highly versatile scaffold in drug discovery , 2022, Archiv der Pharmazie.

[3]  V. Boyarskiy,et al.  Synthesis, Structure, and Antiproliferative Action of 2-Pyridyl Urea-Based Cu(II) Complexes , 2022, Biomedicines.

[4]  V. Boyarskiy,et al.  Cyclometallated Platinum(II) Complexes for Obtaining Phenyl-Containing Silicone Rubbers via Catalytic Hydrosilylation Reaction , 2022, Russian Journal of General Chemistry.

[5]  E. Grachova,et al.  Tuning the Luminescence of Transition Metal Complexes with Acyclic Diaminocarbene Ligands , 2022, Inorganic Chemistry Frontiers.

[6]  V. Boyarskiy,et al.  Deprotonated diaminocarbene platinum complexes for thermoresponsive luminescent silicone materials: both catalysts and luminophores. , 2021, Dalton transactions.

[7]  V. Boyarskiy,et al.  π–π Noncovalent Interaction Involving 1,2,4- and 1,3,4-Oxadiazole Systems: The Combined Experimental, Theoretical, and Database Study , 2021, Molecules.

[8]  R. Czarnomysy,et al.  Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments , 2021, International journal of molecular sciences.

[9]  R. Trifonov,et al.  Diaminocarbene Complexes of Palladium(II) Containing 2-Aminooxazole and 2-Aminothiazole Heterocyclic Ligands as Potential Antitumor Agents , 2021, Pharmaceutical Chemistry Journal.

[10]  J. Pichel,et al.  Luminescent cyclometalated platinum(II) complexes with acyclic diaminocarbene ligands: structural, photophysical and biological properties. , 2021, Dalton transactions.

[11]  G. Chauhan,et al.  Current Advancement in the Oxadiazole-Based Scaffolds as Anticancer Agents , 2021, Polycyclic Aromatic Compounds.

[12]  V. Nesterov,et al.  Highly Sterically Encumbered Gold Acyclic Diaminocarbene Complexes: Overriding Electronic Control in Regiodivergent Gold Catalysis , 2020, Organometallics.

[13]  V. Sharoyko,et al.  Arene–Ruthenium(II) Complexes Containing 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives and Tryptanthrin-6-oxime: Synthesis, Characterization, Cytotoxicity, and Catalytic Transfer Hydrogenation of Aryl Ketones , 2020, ACS omega.

[14]  V. Boyarskiy,et al.  Water soluble palladium(ii) and platinum(ii) acyclic diaminocarbene complexes: solution behavior, DNA binding, and antiproliferative activity , 2020 .

[15]  E. Pidko,et al.  Phosphorescent Iridium(III) Complexes with Acyclic Diaminocarbene Ligands as Chemosensors for Mercury. , 2020, Inorganic chemistry.

[16]  M. Suckow,et al.  Structure-Activity Relationship for the Oxadiazole Class of Antibacterials. , 2019, ACS medicinal chemistry letters.

[17]  K. Luzyanin,et al.  Reactivity of acyclic diaminocarbene ligands , 2019, Coordination Chemistry Reviews.

[18]  V. Boyarskiy,et al.  Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C H activation of N-oxides , 2019, Tetrahedron Letters.

[19]  A. Terenzi,et al.  Metal Complexes of Oxadiazole Ligands: An Overview , 2019, International journal of molecular sciences.

[20]  V. Sharoyko,et al.  1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer , 2019, International journal of molecular sciences.

[21]  C. Supuran,et al.  Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment. , 2019, European journal of medicinal chemistry.

[22]  P. Ghosh,et al.  Palladium Acyclic Diaminocarbene (ADC) Triflate Complexes as Effective Precatalysts for the Hiyama Alkynylation/Cyclization Reaction Yielding Benzofuran Compounds: Probing the Influence of the Triflate Co-Ligand in the One-Pot Tandem Reaction , 2019, ChemistrySelect.

[23]  S. Radulović,et al.  Antitumor activity of organoruthenium complexes with chelate aromatic ligands, derived from 1,10-phenantroline: Synthesis and biological activity. , 2019, Journal of inorganic biochemistry.

[24]  P. Świątek,et al.  Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole , 2018, Molecules.

[25]  V. P. Boyarskii,et al.  Formation of Homo- and Heteronuclear Platinum(II) and Palladium(II) Carbene Complexes in the Reactions of Coordinated Isocyanides with Aminothiazaheterocycles , 2018, Russian Journal of General Chemistry.

[26]  P. Ghosh,et al.  Binuclear Fused 5-membered Palladacycle and Palladium Complex of Amido-Functionalized N-heterocyclic Carbene Precatalysts for the One-Pot Tandem Hiyama Alkynylation/Cyclization Reactions , 2018, ChemistrySelect.

[27]  B. A. Fuller,et al.  Visible light accelerated hydrosilylation of alkynes using platinum-[acyclic diaminocarbene] photocatalysts. , 2018, Chemical communications.

[28]  A. Tskhovrebov,et al.  Polystyrene-Supported Acyclic Diaminocarbene Palladium Complexes in Sonogashira Cross-Coupling: Stability vs. Catalytic Activity , 2018 .

[29]  Zhi‐Feng Zhang,et al.  Anticancer metal-N-heterocyclic carbene complexes of gold, platinum and palladium. , 2018, Current opinion in chemical biology.

[30]  P. Ghosh,et al.  One-Pot Tandem Hiyama Alkynylation/Cyclizations by Palladium(II) Acyclic Diaminocarbene (ADC) Complexes Yielding Biologically Relevant Benzofuran Scaffolds , 2018, ACS omega.

[31]  Bruno G. M. Rocha,et al.  Platinum Complexes with Chelating Acyclic Aminocarbene Ligands Work as Catalysts for Hydrosilylation of Alkynes , 2018, ACS omega.

[32]  Ž. Bugarčić,et al.  Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives. , 2017, European journal of medicinal chemistry.

[33]  M. Shahar Yar,et al.  Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. , 2017, European journal of medicinal chemistry.

[34]  V. Boyarskiy,et al.  Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C–H functionalization of pyridine N-oxides , 2016 .

[35]  V. Boyarskiy,et al.  Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)PdII Complexes. , 2016, Journal of the American Chemical Society.

[36]  F. Huq,et al.  Comprehensive review on tumour active palladium compounds and structure–activity relationships , 2016 .

[37]  I. Balova,et al.  Synthesis and Simple Immobilization of Palladium(II) Acyclic Diaminocarbene Complexes on Polystyrene Support as Efficient Catalysts for Sonogashira and Suzuki–Miyaura Cross-Coupling , 2016 .

[38]  S. Lippard,et al.  The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. , 2016, Chemical reviews.

[39]  Ping Chen,et al.  RNA interferences targeting the Fanconi anemia/BRCA pathway upstream genes reverse cisplatin resistance in drug-resistant lung cancer cells , 2015, Journal of Biomedical Science.

[40]  S. Bajaj,et al.  1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. , 2015, European journal of medicinal chemistry.

[41]  V. Boyarskiy,et al.  Metal-mediated and metal-catalyzed reactions of isocyanides. , 2015, Chemical reviews.

[42]  G. Sheldrick Crystal structure refinement with SHELXL , 2015, Acta crystallographica. Section C, Structural chemistry.

[43]  G. Sheldrick SHELXT – Integrated space-group and crystal-structure determination , 2015, Acta crystallographica. Section A, Foundations and advances.

[44]  N. Abbas,et al.  Oxadiazoles as Privileged Motifs for Promising Anticancer Leads: Recent Advances and Future Prospects , 2014, Archiv der Pharmazie.

[45]  Hartmut Yersin,et al.  Photophysical properties of cyclometalated Pt(II) complexes: counterintuitive blue shift in emission with an expanded ligand π system. , 2013, Inorganic chemistry.

[46]  V. Boyarskiy,et al.  Acyclic diaminocarbenes (ADCs) as a promising alternative to N-heterocyclic carbenes (NHCs) in transition metal catalyzed organic transformations , 2012 .

[47]  Stephen D. Pickett,et al.  The developability of heteroaromatic and heteroaliphatic rings – do some have a better pedigree as potential drug molecules than others? , 2012 .

[48]  M. Barbazanges,et al.  Chiral Acyclic Diaminocarbene Complexes: a New Opportunity for Gold Asymmetric Catalysis , 2012 .

[49]  Sachin Handa,et al.  Enantioselective alkynylbenzaldehyde cyclizations catalyzed by chiral gold(I) acyclic diaminocarbene complexes containing weak Au-arene interactions. , 2012, Angewandte Chemie.

[50]  Jonas Boström,et al.  Oxadiazoles in medicinal chemistry. , 2012, Journal of medicinal chemistry.

[51]  C. Locht,et al.  Ethionamide boosters. 2. Combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1,2,4-oxadiazole EthR inhibitors. , 2011, Journal of medicinal chemistry.

[52]  Richard J. Gildea,et al.  OLEX2: a complete structure solution, refinement and analysis program , 2009 .

[53]  A. Pombeiro,et al.  Coupling between 3-Iminoisoindolin-1-ones and Complexed Isonitriles as a Metal-Mediated Route to a Novel Type of Palladium and Platinum Iminocarbene Species , 2008 .

[54]  L. M. Slaughter “COVALENT SELF-ASSEMBLY” OF ACYCLIC DIAMINOCARBENE LIGANDS AT METAL CENTERS , 2008 .

[55]  A. Pombeiro,et al.  Synthesis of (1,2,4‐Oxadiazole)palladium(II) Complexes by [2 + 3] Cycloaddition of Nitrile Oxides to Organonitriles in the Presence of PdCl2 , 2005 .

[56]  A. Pombeiro,et al.  A Route to 1,2,4-oxadiazoles and their complexes via platinum-mediated 1,3-dipolar cycloaddition of nitrile oxides to organonitriles. , 2003, Inorganic chemistry.

[57]  O. Potapova,et al.  The Jun Kinase/Stress-activated Protein Kinase Pathway Functions to Regulate DNA Repair and Inhibition of the Pathway Sensitizes Tumor Cells to Cisplatin* , 1997, The Journal of Biological Chemistry.

[58]  A. V. Zelewsky,et al.  Cyclometalated complexes of platinum(II): homoleptic compounds with aromatic C,N ligands , 1987 .

[59]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.