Akhil R. Chakravarty

An Iron Complex of Dipyridophenazine as a Potent Photocytotoxic Agent in Visible Light

Ternary iron(III) complexes [FeL(B)] (1-3) of a trianionic tetradentate phenolate-based ligand (L) and phenanthroline base (B), namely, 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), have been prepared and structurally characterized and their DNA binding, cleavage, and photocytotoxic properties studied. The complexes with a FeN(3)O(3) core show the Fe(III)/Fe(II) redox couple near -0.6 V in DMF, a magnetic moment value of approximately 5.9 micro(B), and a binding propensity to both calf thymus DNA and bovine serum albumin (BSA) protein. They exhibit red-light-induced DNA cleavage activity following a metal-assisted photoredox pathway forming HO(*) radicals but do not show any photocleavage of BSA in UV-A light. Complex 3 displays photocytotoxicity in the human cervical cancer cell line (HeLa) and human keratinocyte cell line (HaCaT) with respective IC(50) values of 3.59 microM and 6.07 microM in visible light and 251 nM and 751 nM in UV-A light of 365 nm. No significant cytotoxicity is observed in the dark. The photoexposed HeLa cells, treated prior with complex 3, have shown marked changes in nuclear morphology as demonstrated by Hoechst 33258 nuclear stain. Generation of reactive oxygen species has been evidenced from the fluorescence enhancement of dichlorofluorescein upon treatment with 3 followed by photoexposure. Nuclear chromatin cleavage has been observed in acridine orange/ethidium bromide dual staining of treated HeLa cells and from alkaline single-cell gel electrophoresis. Caspase 3/7 activity in HeLa cells has been found to be upregulated by only 4 fold after photoirradiation, signifying the fact that cell death through a caspase 3/7 dependent pathway may not be solely operative.

Photodynamic Effect in Near-IR Light by a Photocytotoxic Iron(III) Cellular Imaging Agent

A red light for cancer cells: an iron(III) complex (1, see picture) that contains an anthracenyl fluorophore moiety and a catecholate ligand is a potent, metal-based PDT agent that efficiently photocleaves DNA in near-infrared light, has significant nuclear uptake, and high photocytotoxicity in red light by an apoptotic pathway in HeLa and MCF-7 cancer cells.

Metal Complexes of Curcumin for Cellular Imaging, Targeting, and Photoinduced Anticancer Activity

Curcumin is a polyphenolic species. As an active ingredient of turmeric, it is well-known for its traditional medicinal properties. The therapeutic values include antioxidant, anti-inflammatory, antiseptic, and anticancer activity with the last being primarily due to inhibition of the transcription factor NF-κB besides affecting several biological pathways to arrest tumor growth and its progression. Curcumin with all these positive qualities has only remained a potential candidate for cancer treatment over the years without seeing any proper usage because of its hydrolytic instability involving the diketo moiety in a cellular medium and its poor bioavailability. The situation has changed considerably in recent years with the observation that curcumin in monoanionic form could be stabilized on binding to a metal ion. The reports from our group and other groups have shown that curcumin in the metal-bound form retains its therapeutic potential. This has opened up new avenues to develop curcumin-based metal complexes as anticancer agents. Zinc(II) complexes of curcumin are shown to be stable in a cellular medium. They display moderate cytotoxicity against prostate cancer and neuroblastoma cell lines. A similar stabilization and cytotoxic effect is reported for (arene)ruthenium(II) complexes of curcumin against a variety of cell lines. The half-sandwich 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (RAPTA)-type ruthenium(II) complexes of curcumin are shown to be promising cytotoxic agents with low micromolar concentrations for a series of cancer cell lines. In a different approach, cobalt(III) complexes of curcumin are used for its cellular delivery in hypoxic tumor cells using intracellular agents that reduce the metal and release curcumin as a cytotoxin. Utilizing the photophysical and photochemical properties of the curcumin dye, we have designed and synthesized photoactive curcumin metal complexes that are used for cellular imaging by fluorescence microscopy and damaging the cancer cells on photoactivation in visible light while being minimally toxic in darkness. In this Account, we have made an attempt to review the current status of the chemistry of metal curcumin complexes and present results from our recent studies on curcumin complexes showing remarkable in vitro photocytotoxicity. The undesirable dark toxicity of the complexes can be reduced with suitable choice of the metal and the ancillary ligands in a ternary structure. The complexes can be directed to specific subcellular organelles. Selectivity by targeting cancer cells over normal cells can be achieved with suitable ligand design. We expect that this methodology is likely to provide an impetus toward developing curcumin-based photochemotherapeutics for anticancer treatment and cure.

Oxovanadium(IV)-based near-IR PDT agents: Design to biological evaluation

An oxovanadium(IV) complex of dipyridophenazine, as a potent metal-based PDT agent, shows efficient DNA photocleavage activity at near-IR region and high photocytotoxicity in both UV-A and visible light in HeLa cells.

Metal-assisted red light-induced efficient DNA cleavage by dipyridoquinoxaline-copper(II) complex.

Complete cleavage of double stranded pUC19 DNA by the complex [Cu(dpq)2(H2O)](ClO4)2 (dpq, dipyridoquinoxaline) has been observed on irradiation at 694 nm from a pulsed ruby laser, assisted by the metal d-band transition as well as the quinoxaline triplet states in the absence of any external additives.

New preparations and molecular structures of cis-MCl2(Ph2PCH2PPh2)2, M = Ru, Os and trans-RuCl2(Ph2PCH2PPh2)2

Abstract The title compounds were made by reacting bis(diphenylphosphino)methane (dppm) with reduced solutions of OsCl64− and Ru2OCl104−. The crystal and molecular structures of these compounds have been determined form three-dimensional X-ray study. The cis-isomers crystallize with one CHCl3 per molecule of the complex. All three compounds crystallize in the monoclinic space group P21/n with unit cell dimensions as follows: Cis-OsCl2(dppm)2·CHCl3: a = 13.415(4) A, b = 22.859(4) A, c = 16.693(3) A, β = 105.77(3)°, V = 4926(3) A3, Z = 4. cis-RuCl2(dppm)2·CHCl3: a = 13.442(3) A, b = 22.833(7) A, c = 16.750(4) A, β = 105.53(2)°, V = 4953(3) A3, Z = 4. trans-RuCl2(dppm)2: a = 11.368(7) A, b = 10.656(6) A, c = 18.832(12) A; β = 103.90(6)°, V = 2213(7) A3; Z = 2. The structures were refined to R = 0.044 (Rw = 0.055) for cis-OsCl2(dppm)2·CHCl3; R = 0.065 (Rw = 0.079) for cis-RuCl2(dppm)2·CHCl3 and R = 0.028 (Rw = 0.038) for trans-RuCl2(dppm)2. The complexes are six coordinate with stable four-membered chelate rings. The PMP angle in the chelate rings is ca. 71° in each case.

Synthesis, crystal structures and properties of ternary copper(II) complexes having 2,2′-bipyridine and α-amino acid salicylaldiminates as models for the type-2 sites in copper oxidases

Abstract Ternary copper(II) complexes [Cu(salgly)(bpy)]·4H 2 O ( 1 ·4H 2 O), [Cu(salala)(bpy)]·4H 2 O·( 2 ·4H 2 O) and [Cu(salphe)(bpy)] ( 3 ), where salgly, salala and salphe are tridentate Schiff base ligands derived from the condensation of salicylaldehyde with glycine, l -alanine and l -phenylalanine, respectively, and bpy is 2,2′-bipyridine, are prepared and structurally characterized. Crystal structures of the complexes display a distorted square-pyramidal (4+1) coordination geometry in which the ONO-donor Schiff base is bonded to the metal in the basal plane. The chelating bpy ligand displays axial-equatorial mode of bonding. Complexes 1 and 2 show chemically significant hydrogen bonding interactions. In addition, complex 2 exhibits π–π stacking, while complex 3 shows attractive CH(imine)–π (phenyl) non-covalent interactions. The one-electron paramagnetic complexes display axial EPR spectra in DMF-glass at 77 K indicating a {d x 2 − y 2 } 1 ground state. The complexes show a d–d band near 670 nm and a charge transfer band near 440 nm in methanol. The complexes are redox active and exhibit a quasi-reversible Cu(II)–Cu(I) couple in DMF-0.1 M TBAP near −0.8 V versus SCE. The complexes are catalytically active in the oxidation of ascorbic acid by dioxygen. The process which is effective with a mole ratio of ascorbic acid to complex as approximately 30, models the ascorbate oxidation property of the type 2 sites in ascorbate oxidase and dopamine β-hydroxylase. The complexes with a N 3 O 2 coordination environment model the active site structure in amine oxidase and mediate deamination reactions in which benzylamine gets oxidized to benzaldehyde in the presence of hydrogen peroxide.

Iron(III) Schiff base complexes of arginine and lysine as netropsin mimics showing AT-selective DNA binding and photonuclease activity

Iron(III) complexes [Fe(L)(2)]Cl (1-3), where L is monoanionic N-salicylidene-arginine (sal-argH for 1), hydroxynaphthylidene-arginine (nap-argH for 2) and N-salicylidene-lysine (sal-lysH for 3), were prepared and their DNA binding and photo-induced DNA cleavage activity studied. Complex 3 as its hexafluorophosphate salt [Fe(sal-lysH)(2)](PF(6)).6H(2)O (3a) was structurally characterized by single crystal X-ray crystallography. The crystals belonged to the triclinic space group P-1. The complex has two tridentate ligands in FeN(2)O(4) coordination geometry with two pendant cationic amine moieties. Complexes 1 and 2 with two pendant cationic guanidinium moieties are the structural models for the antitumor antibiotics netropsin. The complexes are stable and soluble in water. They showed quasi-reversible Fe(III)/Fe(II) redox couple near 0.6V in H(2)O-0.1M KCl. The high-spin 3d(5)-iron(III) complexes with mu(eff) value of approximately 5.9 mu(B) displayed ligand-to-metal charge transfer electronic band near 500nm in Tris-HCl buffer. The complexes show binding to Calf Thymus (CT) DNA. Complex 2 showed better binding propensity to the synthetic oligomer poly(dA).poly(dT) than to CT-DNA or poly(dG).poly(dC). All the complexes displayed chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent and cleaved supercoiled pUC19 DNA to its nicked circular form. They exhibited photo-induced DNA cleavage activity in UV-A light and visible light via a mechanistic pathway that involves the formation of reactive hydroxyl radical species.

Arene ruthenium complexes of N,N′- and N,O-donor schiff base ligands: an X-ray structure of [(η6-p-cymene) RuCl(C5,H4N-2-CHNC6H4-p-Me)Cl·C6H6·H2O

Arene ruthenium(II) Schiff base complexes of formulations [(η -p-cymene)RuCl(C5H4N-2-CH=NC6H4-p-X)](ClO4) (1) and [(η6-p-cymene)RuCl(O-o-C6H4CH=NC6H4-p-X)] (2) (X = H, Me, OMe, NO2, Cl) were prepared by reacting [(η6-p-cymene)RuCl2]2 with corresponding pyridine-2-carboxaldimines and sodium salts of salicylaldimines in dry THF, respectively. Complex 1 is isolated as a perchlorate salt. The molecular structure of [(η6-p-cymene)RuCl(C5H4 N-2-CH=NC6H4-p-Me)]Cl·C6H6·H2O has been determined by X-ray crystallography. The complex contains an η6-p-cymene group, a chloride and a bidentate chelating Schiff base ligand.

Transfer hydrogenation of acetophenone promoted by (arene)ruthenium(II) reduced Schiff base complexes: an X-ray structure of [(η6-p-cymene)RuCl(OC6H4-2-CH2NHC6H4-p-Me)]

Arene ruthenium(II) reduced Schiff base complexes of formulation