Different Modes of Acid-Promoted Cyclooligomerization of 4‑(4-Thiosemicarbazido)butan-2-one Hydrazone: 14-Membered versus 28-Membered Polyazamacrocycle Formation

Unprecedented self-assembly of a novel 14-membered cyclic bis-thiosemicarbazone or/and a 28-membered cyclic tetrakis-thiosemicarbazone upon acid-promoted cyclooligomerization of 4-(4-thiosemicarbazido)butan-2-one hydrazone has been discovered. A thorough study of the influence of various factors on the direction of macrocyclization provided the optimal conditions for the highly selective formation of each of the macrocycles in excellent yields. Plausible pathways for macrocyclizations have been discussed. The macrocycle precursor was prepared by the reaction of readily available 4-isothiocyanatobutan-2-one with an excess of hydrazine

Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs

The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization (1H and 13C NMR, UV–vis, IR), ESI-mass spectrometry, and single-crystal X-ray diffraction analysis of a new ring system of medicinal significance, 5,6,7,9-tetrahydro-8H-indolo[3,2-e]benzazocin-8-one, and a series of derived potential ligands (HL1–HL5), as well as ruthenium(II), osmium(II), and copper(II) complexes (1a, 1b, and 2–5). The stability of compounds in 1% DMSO aqueous solutions has been confirmed by 1H NMR and UV–vis spectroscopy measurements. The antiproliferative activity of HL1–HL5 and 1a, 1b, and 2–5 was evaluated by in vitro cytotoxicity tests against four cancer cell lines (LS-174, HCT116, MDA-MB-361, and A549) and one non-cancer cell line (MRC-5). The lead compounds HL5 and its copper(II) complex 5 were 15× and 17×, respectively, more cytotoxic than cisplatin against human colon cancer cell line HCT116. Annexin V-FITC apoptosis assay showed dominant apoptosis inducing potential of both compounds after prolonged treatment (48 h) in HCT116 cells. HL5 and 5 were found to induce a concentration- and time-dependent arrest of cell cycle in colon cancer cell lines. Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL5 and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC50 = 1.4–6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs

Palladium Complexes of <i>N</i>,<i>N</i>′‑Bis(2-aminoethyl)oxamide (H₂L): Structural (Pd^IIL, Pd^II₂L₂, and Pd^IVLCl₂), Electrochemical, Dynamic ¹H NMR, and Cytotoxicity Studies

The monomeric (PdL·2H₂O) and dimeric (Pd₂L₂·7H₂O) palladium­(II) complexes of <i>N</i>,<i>N</i>′-bis­(2-aminoethyl)­oxamide (H₂L) were isolated, and their structures were established by single-crystal X-ray diffraction. Both compounds display identical <i>cis-</i>(2N_amide + 2N_amine) coordination environments of the metal ion. The dimer, representing a combination of two PdL species with an open lateral chelate ring, has an “open clamshell”-like structure. The intramolecular metal–metal separation in Pd₂L₂ (3.215 Å) is slightly shorter than the sum of the van der Waals radii of the palladium­(II) atoms. The dimeric complex is relatively stable to dissociation, and its spectral features in aqueous solutions have been compared to those of the monomeric complex. A ¹H NMR spectroscopic study revealed the presence of the dynamic conformational exchange process assigned to a turning of the dimeric molecule “inside out” with an activation energy of 65 kJ/mol. Cyclic voltammetry of PdL in perchlorate-, chloride-, and sulfate-containing electrolytes revealed two-electron oxidation of the palladium center. For the dimeric complex similar, though irreversible, oxidation to the palladium­(IV) state was observed in NaCl electrolyte. At the same time, in NaClO₄ or Na₂SO₄ solutions oxidation of Pd₂L₂ occurs in two distinct steps. The first step is quasi-reversible and can be assigned to the formation of species in an intermediate Pd^IIIPd^III state. Monomeric palladium­(IV) complex Pd^IVLCl₂ was generated via chemical oxidation of Pd^IIL by peroxodisulfate in the presence of chloride ions and structurally characterized. The related M^IIL complexes (M = Pd, Ni, Cu) showed low cytotoxicity in human cancer cell lines AGS (gastric adenocarcinoma) and HCT116 (colorectal carcinoma) with IC₅₀ values from 204 to 525 μM, while the proligand H₂L was devoid of antiproliferative activity (IC₅₀ > 1000 μM)

Intermolecular Reactions of a Foiled Carbene with Carbonyl Compounds: The Effects of Trishomocyclopropyl Stabilization

<i>endo</i>-Tricyclo­[3.2.1.0^2,4]­oct-8-ylidene is a foiled carbene reaction intermediate. It was generated by thermolyzing Δ³-1,3,4-oxadiazoline precursors dissolved in benzaldehyde and acetophenone. The products appear to stem from direct insertion of the carbene’s divalent C atom into the α-bonds of the carbonyl compounds; however, this is only superficial. The strict stereochemistry observed is due to the topologies of the reaction intermediates of the proposed two-step mechanism. Bimolecular nucleophilic addition generates bent 1,3-zwitterions. The neutral reaction intermediates undergo pinacolic rearrangements to form the observed adducts. Product ratios reflect the migratory aptitudes of the carbonyl compounds’ α-substituents. The carbene reaction was modeled using DFT. The singlet carbene’s bicoordinate C atom bends 31° toward the <i>endo</i>-fused cyclopropane bond, elongating it to <i>r</i> = 1.69 Å. The resulting trishomocyclopropyl HOMO{−1} is a three-center two-electron bond responsible for the electron-deficient carbene’s nucleophilicity. Its calculated properties are consistent with this assertion: (1) singlet–triplet (Δ<i>E</i>_S–T) energy gap of −25 kcal/mol, (2) gas-phase proton affinity (PA) value of 272 kcal/mol, (3) hard and soft acid and base (HSAB) Δ<i>N</i> value of −0.2 in its initial reaction with the carbonyl compounds, and (4) negative frontier orbital interaction values ΔΔ<i>E</i>(PhC­(O)­H) = −4.38 eV and ΔΔ<i>E</i>(PhC­(O)­Me) = −3.97 eV

Intermolecular Reactions of a Foiled Carbene with Carbonyl Compounds: The Effects of Trishomocyclopropyl Stabilization

<i>endo</i>-Tricyclo­[3.2.1.0^2,4]­oct-8-ylidene is a foiled carbene reaction intermediate. It was generated by thermolyzing Δ³-1,3,4-oxadiazoline precursors dissolved in benzaldehyde and acetophenone. The products appear to stem from direct insertion of the carbene’s divalent C atom into the α-bonds of the carbonyl compounds; however, this is only superficial. The strict stereochemistry observed is due to the topologies of the reaction intermediates of the proposed two-step mechanism. Bimolecular nucleophilic addition generates bent 1,3-zwitterions. The neutral reaction intermediates undergo pinacolic rearrangements to form the observed adducts. Product ratios reflect the migratory aptitudes of the carbonyl compounds’ α-substituents. The carbene reaction was modeled using DFT. The singlet carbene’s bicoordinate C atom bends 31° toward the <i>endo</i>-fused cyclopropane bond, elongating it to <i>r</i> = 1.69 Å. The resulting trishomocyclopropyl HOMO{−1} is a three-center two-electron bond responsible for the electron-deficient carbene’s nucleophilicity. Its calculated properties are consistent with this assertion: (1) singlet–triplet (Δ<i>E</i>_S–T) energy gap of −25 kcal/mol, (2) gas-phase proton affinity (PA) value of 272 kcal/mol, (3) hard and soft acid and base (HSAB) Δ<i>N</i> value of −0.2 in its initial reaction with the carbonyl compounds, and (4) negative frontier orbital interaction values ΔΔ<i>E</i>(PhC­(O)­H) = −4.38 eV and ΔΔ<i>E</i>(PhC­(O)­Me) = −3.97 eV

Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2‑<i>c</i>]quinolinePiperazine Hybrids

In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline–piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline–piperazine hybrids L^1–3 were prepared <i>in situ</i> and isolated as six ruthenium and osmium complexes [(η⁶-<i>p</i>-cymene)­M­(L^1–3)­Cl]­Cl, where L¹ = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-2-<i>N</i>-amine, M = Ru ([<b>1a</b>]­Cl), Os ([<b>1b</b>]­Cl), L² = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-4-<i>N</i>-amine, M = Ru ([<b>2a</b>]­Cl), Os ([<b>2b</b>]­Cl), L³ = 6-(4-methylpiperazin-1-yl)-<i>N</i>-(pyridin-2-yl-methylene)-11<i>H</i>-indolo­[3,2-<i>c</i>]­quinolin-8-<i>N</i>-amine, M = Ru ([<b>3a</b>]­Cl), Os ([<b>3b</b>]­Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV–vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [<b>1a</b>,<b>b</b>]­Cl–[<b>3a,b</b>]Cl was examined <i>in vitro</i> and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([<b>2a</b>]Cl and [<b>2b</b>]­Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure–activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline–piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents

En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of <i>trans</i>-[Os^IVCl₄(Hazole)₂]

By controlled Anderson type rearrangement reactions complexes of the general formula <i>trans</i>-[Os^IVCl₄(Hazole)₂], where Hazole = 1<i>H</i>-pyrazole, 2<i>H</i>-indazole, 1<i>H</i>-imidazole, and 1<i>H</i>-benzimidazole, have been synthesized. Note that 2<i>H</i>-indazole tautomer stabilization in <i>trans</i>-[Os^IVCl₄(2<i>H</i>-indazole)₂] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H₂ind)[Ru^IIICl₄(Hind)₂], where Hind = 1<i>H</i>-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of <i>trans</i>-[Os^IVCl₄(Hpz)₂] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported

En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of <i>trans</i>-[Os^IVCl₄(Hazole)₂]

By controlled Anderson type rearrangement reactions complexes of the general formula <i>trans</i>-[Os^IVCl₄(Hazole)₂], where Hazole = 1<i>H</i>-pyrazole, 2<i>H</i>-indazole, 1<i>H</i>-imidazole, and 1<i>H</i>-benzimidazole, have been synthesized. Note that 2<i>H</i>-indazole tautomer stabilization in <i>trans</i>-[Os^IVCl₄(2<i>H</i>-indazole)₂] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H₂ind)[Ru^IIICl₄(Hind)₂], where Hind = 1<i>H</i>-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of <i>trans</i>-[Os^IVCl₄(Hpz)₂] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported

Strategy to Optimize the Biological Activity of Arene Ruthenium Metalla-Assemblies

Three new dinuclear arene ruthenium metalla-clips of the general formula [(<i>p</i>-cymene)₂­Ru₂Cl₂­(μ-L)] have been prepared from [(<i>p</i>-cymene)₂­Ru₂Cl₂­(μ-Cl)₂] and H₂L organic linkers (H₂L^a = diethyl-1,2-diazenedicarboxylate, H₂L^b = <i>N</i>,<i>N′</i>-bis­(2-hydroxy­ethyl)­oxamide, H₂L^c = <i>N</i>,<i>N′</i>-bis­{2-(2-hydroxy­ethoxy)­ethyl}­ethanediamide). The bis-chelating bridging-linkers possess two functional groups that can be synthetically modified for physico-chemical optimizations. Reaction of these three dinuclear metalla-clips with 4,4′-bipyridine, 1,2-bis­(4-pyridyl)­ethylene, and 4,4′-azopyridine affords, in the presence of AgCF₃SO_3, nine tetracationic tetranuclear metalla-rectangles. Similarly, the tridentate ligands 2,4,6-tris­(4-pyridyl)-1,3,5-triazine and 1,3,5-tris­{2-(4-pyridyl)­vinyl}­benzene were used to generate six hexacationic hexanuclear metalla-prisms. All metalla-assemblies and the dinuclear complexes were evaluated as anticancer agents against cancerous (A2780) and noncancerous (HEK293) cell lines, showing an excellent selectivity for cancer cells. The IC₅₀ values of the cationic metalla-assemblies were typically <1 μM, whereas, for the neutral dinuclear metalla-clips, the IC₅₀ values were >100 μM

Osmium(III) Analogues of KP1019: Electrochemical and Chemical Synthesis, Spectroscopic Characterization, X‑ray Crystallography, Hydrolytic Stability, and Antiproliferative Activity

A one-electron reduction of osmium­(IV) complexes <i>trans</i>-[Os^IVCl₄(Hazole)₂], where Hazole = 1<i>H</i>-pyrazole ([<b>1</b>]⁰), 2<i>H</i>-indazole ([<b>2</b>]⁰), 1<i>H</i>-imidazole ([<b>3</b>]⁰), and 1<i>H</i>-benzimidazole ([<b>4</b>]⁰), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)­[<i>trans</i>-Os^IIICl₄(Hazole)₂], where cation = H₂pz⁺ (H₂pz­[<b>1</b>]), H₂ind⁺ (H₂ind­[<b>2</b>]), H₂im⁺ (H₂im­[<b>3</b>]), Ph₄P⁺ (Ph₄P­[<b>3</b>]), <i>n</i>Bu₄N⁺ (<i>n</i>Bu₄N­[<b>3</b>]), H₂bzim⁺ (H₂bzim­[<b>4</b>]), Ph₄P⁺ (Ph₄P­[<b>4</b>]), and <i>n</i>Bu₄N⁺ (<i>n</i>Bu₄N­[<b>4</b>]). All complexes were characterized by elemental analysis, ¹H NMR spectroscopy, electrospray ionization mass spectrometry, UV–vis spectroscopy, cyclic voltammetry, while H₂pz­[<b>1</b>], H₂ind­[<b>2</b>], and <i>n</i>Bu₄[<b>3</b>], in addition, by X-ray diffraction. The reduced species [<b>1</b>]⁻ and [<b>4</b>]⁻ are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5′-dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, MDA-MB-453, and LS-174) and one noncancerous cell line (MRC-5) were performed, and the results were discussed and compared to those for KP1019 and cisplatin. Benzannulation in complexes with similar structure enhances antitumor activity by several orders of magnitude, implicating different mechanisms of action of the tested compounds. In particular, complexes H₂ind­[<b>2</b>] and H₂bzim­[<b>4</b>] exhibited significant antiproliferative activity <i>in vitro</i> when compared to H₂pz­[<b>1</b>] and H₂im­[<b>3</b>]