Chemistry of rhenium(I) tricarbonyl complexes of biomedical relevance

fac-[ReI(CO)3L]n complexes serve as models for short-lived fac-[99mTcI(CO)3L] imaging tracers. Dangling groups on L, needed to achieve desirable biodistribution, complicate the NMR spectra, which are not readily understood. In fac-[ReI(CO)3L]+ with less complicated L, NH groups (exo-NH) projecting toward the L face sometimes showed an upfield shift attributable to steric shielding of the exo-NH group from the solvent by the chelate rings. To investigate whether exo-NH groups in six-membered rings exhibit the same effect and whether the presence of dangling groups alters the effect, we prepared new fac-[Re(CO)3L]n complexes that allow direct comparisons of exo-NH shifts for six-membered vs. five-membered chelate rings. The use of anions as probes, including the new use of the [ReBr6]2– anion as a paramagnetic outer-sphere H-bonding shift reagent, establishes that these NH protons are not well solvated. Lack of solvation, induced by chelate ring bulk, accounts for the upfield shift. To evaluate syntheses of fac-[Re(CO)3L]+ complexes in organic solvents, we treated fac-[Re(CO)3(CH3CN)3]PF6/BF4 in acetonitrile with triamine ligands (L). When L had two primary or two tertiary terminal amine groups, the expected fac-[Re(CO)3L]+ complexes formed. Treatment of fac-[Re(CO)3(CH3CN)3]+ with various tridentate amine ligands has produced several novel compounds, which most likely arise from reaction of the coordinated nitrile with ligand terminal amines. The new compounds advance our understanding of the spectral and structural properties of Re analogues of 99mTc radiopharmaceuticals. In fac-[Re(CO)3(5,5¢-Me2bipy)(HNC(CH3)NHR)]BF4 complexes, the monodentate amidine ligand adopts the E, E¢, and Z, but not the Z¢ configuration in solution. Both amidine CN bonds have double-bond character, leading to slow isomerization on the NMR time scale. The equilibrium favors the E¢ isomer as NHR rises above a threshold size or when stacking can occur. The structural characterization of fac-[Re(CO)3L]+ complexes bearing novel ligands having a central sulfonamide group and two pyridine rings has revealed that the central N of the tertiary sulfonamide group binds to Re. These are among the few structurally characterized complexes with a tertiary (neutral) sulfonamide bound to a metal. We show that a sulfonamide can be used to conjugate the {Re(CO)3}+ unit to a porphyrin. The new ligands may be used eventually in 99mTc imaging

Complexes of N, N- and N, N, N- Sulfonamide Ligands as Therapeutic and Diagnostic Agents

Ethylenediamine, diethylenetriamine and dipicolylamine have been used as the carrier ligands to synthesize bidentate (N,N) or tridentate (N,N,N) chelate systems that coordinate with metal centers. The terminal amine groups of ethylenediamine and diethylenetriamine and the central amine group of dipicolylamine can be easily substituted to give sulfonamide ligands having bulky aromatic fragments. In the formation of metal sulfonamides, the sulfonamide nitrogens of primary or secondary sulfonamidesdeprotonate and coordinate with metal centers forming M-N bonds while the free amines coordinate to metal centers through lone pairs. The reported synthetic approaches and the properties of these complexes and ligands are discussed in this review. The bulky sulfonamide moieties bring about unique biological features to the ligand system while enhancing the fluorescent properties of the ligand. The metal center itself incorporates interesting biological features to the complex. These properties of the metal center andthe ligand show a synergistic effect in the complexes that may come in handy when designing therapeutic or diagnostic agents. The increased lipophilicity of the ligands and thereby the complexes will ensure better uptake by target cells making them ideal candidates for biological applications. Keywords: Sulfonamide, ethylenediamine, diethylenetriamine, dipicolylamin

Metal Dipicolylamines and their Biomedical Applications: A Mini Review

Research in synthetic inorganic chemistry demonstrates that metal complexes are widely utilized as therapeutic as well as diagnostic agents. Due to the coordinative saturation, substitutional inertness, and unique redox characteristics, metal polypyridyl complexes have ignited attention and have been exploited in a number of biological and biomedical fields. The polypyridyl ligand, dipicolylamine (DPA) is a symmetrical secondary amine with two pyridyl rings. Delocalization of excited electrons occurs throughout the ligand system due to its conjugated character and the metal-to-ligand charge transfer transitions, resulting in a strong fluorescence signal. The high lipophilic nature of this ligand has proven to improve metal-DPA complex absorption by cell membranes. The N–H amine group in DPA and its analogues have the additional function of allowing hydrogen bonds to form, and deprotonation of this amine has allowed the creation of mononuclear and polynuclear species, with deprotonation of the bridging amine nitrogen also playing a significant role in the coordination sequence. DPA-appended metal complexes have garnered attention in the quest for linkages between magnetic, spectroscopic, structural, and coordination geometries. A number of mononuclear metal-DPA complex crystal structures with four, five, or six coordinated metal centers have been synthesized and explored for their biological properties. This study reviews DPA-derivatized ligand-linked metal complexes as promising cancer, microbial, and fungal inflammatory therapeutics, as well as potential diagnostic agents for fluorescence imaging and radiopharmaceuticals. Keywords: Dipicolylamine, metal complexes, coordination geometries, fluorescent agent

Synthesis, Characterization, and Biological Studies of a Piperidinyl Appended Dipicolylamine Ligand and Its Rhenium Tricarbonyl Complex as Potential Therapeutic Agents for Human Breast Cancer

© 2016 Amali Subasinghe et al. A novel ligand bearing a central piperidinyl sulfonamide group, N(SO2pip)dpa, and its corresponding Re tricarbonyl complex, [Re(CO)3(N(SO2pip)dpa)]+, have been synthesized in good yield. The methylene CH2 signal seen as a singlet (4.54 ppm) in a 1H NMR spectrum of the ligand in DMSO-d6 appears as two doublets (5.39, 5.01 ppm) in a spectrum of the [Re(CO)3(N(SO2pip)dpa)]+ complex and confirms the presence of magnetically nonequivalent protons upon coordination to Re. Structural results revealed that the Re-N bond lengths fall within the normal range establishing coordination of ligand to metal. The presence of intraligand π→π and n→π transitions is indicated by the absorption peaks around 200-250 nm in UV-visible spectra. Absorption peaks in UV-visible spectra around 300 nm for metal complexes were identified as MLCT transitions. The S-N stretch observed as a strong peak at 923 cm-1 for N(SO2pip)dpa appeared at a shorter frequency, at 830 cm-1 in an FTIR spectrum of the [Re(CO)3(N(SO2pip)dpa)]+. The intense fluorescence displayed by the N(SO2pip)dpa ligand has quenched upon coordination to Re. Relatively low IC50 values given by human breast cancer cells, MCF-7, (N(SO2pip)dpa = 139 μM, [Re(CO)3(N(SO2pip)dpa)]+ = 360 μM) indicate that N(SO2pip)dpa and [Re(CO)3(N(SO2pip)dpa)]+ are promising novel compounds that can be further investigated on their usage as potential anticancer agents

Synthesis and Characterization of Novel Diethylenetriamine Based Sulfonamide Ligands and Their Bidentate Platinum(II) Complexes Toward Anticancer Drug Leads

Diethylenetriamine (dienH) is one of the most biologically compatible chelate frameworks. Its hydrophilic amine moiety was functionalized via N-sulfonylation with sulfonyl chloride to produce two novel ligands; N(SO2)(bzd)dienH (L1) and N(SO2)(4-Mebip)dienH (L2) and two reported ligands; N(SO2)(1-nap)dienH (L3) and N(SO2)(2-nap)dienH (L4). Treatment of cis-Pt(DMSO)2Cl2with L1, L2, L3 and L4 afforded four novel neutral complexes [Pt(N(SO2)(bzd)dienH)Cl2] (C1), [Pt(N(SO2)(4-Mebip)dienH)Cl2] (C2), [Pt(N(SO2)(1-nap)dienH)Cl2] (C3) and [Pt(N(SO2)(2-nap)dienH)Cl2] (C4) respectively. All synthesized compounds were characterized by 1H NMR, UV-Vis, FTIR and fluorescence spectroscopy. Aliphatic diethylenetriamine protons of the ligands appeared in the 3.00 -2.30 ppm region in 1H NMR spectra recorded in DMSO-d6. Upon complexation, the appearance of two broad NH peaks between 5.00 -7.00 ppm region and another broad peak between 7.00-8.00 ppm confirmed the bidentatedenticity of the ligands vs tridentate. The formation of metal complexes was further supported by FTIR spectra in which the S-N stretching band for the metal complexes appears at lower wavenumbers compared to that of the corresponding free ligands. Emission spectra were recorded in methanol and intense fluorescence properties were observed in the 331-364 nm range for the ligands, whereas the corresponding Pt complexes showed quenched fluorescence. In vitro cytotoxic effects were investigatedusing sulforhodamine B assay, where L2 (< 10 μg/mL) demonstrated increased levels of cytotoxicity followed by C2 (< 25 μg/mL) and C4 (< 50 μg/mL) to non-small cell lung cancer cells in dose and time-dependent manner, with less or no cytotoxic effects to normal lung cells tested. Among the compounds tested, C1 and C3 displayed comparatively lower but more potent cytotoxic effects on lung cancer cells. Notably, these compounds did not exhibit any toxicity towards normal cells. Thus, they hold promise as lead compounds for the development of chemotherapeutic agents targeting lung cancer. Keywords: Platinum, Sulfonamide, Biphenyl, Benzodioxan, aphthalen

Synthesis, Characterization and Remarkable Anticancer Activity of Rhenium Complexes Containing Biphenyl Appended NNN Donor Sulfonamide Ligands

Neutral and cationic rhenium complexes provide both hydrophilic as well as hydrophobic properties due to the robustness of the tridentate ligand system of biphenyl appended dipicolylamine (N(SO2bip)dpa) and diethylenetriamine (N(SO2bip)dienH) coordinated to the [Re(CO)3]+ core, hold immense potential for the development of metal based anticancer drugs. This was achieved by the synthesis of two ligands (L1: N(SO2bip)dpa and L2: (N(SO2bip)dienH) and their corresponding Re complexes (C1: [Re(CO)3(N(SO2bip)dpa)]PF6 and C2: [Re(CO)3(N(SO2bip)dien)] in good yield and high purity. All four compounds were characterized by 1H NMR, UV-Vis, FTIR spectroscopies and L1, also by single crystal X-ray diffraction. The methylene protons observed as a singlet at (4.59 ppm) in a 1H NMR spectrum of L1 appear as two doublets (5.66 and 4.65 ppm) in the spectrum of C1. The appearance of NH signals at 3.48, 5.17 and 6.69 ppm in the 1H NMR spectrum of C2 confirm the coordination of L2 with Re. The stretching vibration frequencies depicted by the S-N bond at 923 cm-1 for L1 appear towards lower frequencies (821 cm-1) in an FTIR spectrum of C1, while the S-N bond at 943 cm-1 for L2 appears towards higher frequencies (968 cm-1) in C2. In silico assessment of drug likeliness revealed zero violations demonstrating a high likeliness of the ligands to be successful as drug leads. All four compounds have shown very low IC50 values against non-small cell lung cancer cells (NCI-H292). Therefore, L1, C1, L2 and C2 are promising novel compounds that can be further investigated as potential anticancer agents. Keywords: Rhenium Tricarbonyl, Sulfonamide, Anticancer, Fluorescence

2,9,16,23-Tetra­kis(1-methyl­eth­yl)-5,6,11,12,13,14,19,20,25,26,27,28-dodecadehydro­tetra­benzo[a,e,k,o]cyclo­eicosene1

The title compound, C48H40, is a tetra­isopropyl-substituted polyannulenoenyne. The unsubstituted polyannulenoenyne, C36H16 (CSD: RICVEE; CAS: 186494-87-1), has quasi-D 2 (222) symmetry, as determined by least-squares fit (excluding H atoms) to a model optimized in D 2 symmetry by mol­ecular mechanics (r.m.s. deviation = 0.239 Å). The least-squares fits of 36 common C atoms of the title compound (at 90 K) to the parent (at 295 K) and to the optimized model show r.m.s. deviations of 0.419 and 0.426 Å, respectively

Synthesis, Characterization, and BSA-Binding Studies of Novel Sulfonated Zinc-Triazine Complexes

Four Zn(II) complexes containing a pyridyl triazine core (L1 = 3-(2-pyridyl)-5,6-di(2-furyl)-1,2,4-triazine-5′,5″-disulfonic acid disodium salt and L2 = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine-4′,4″-disulfonic acid sodium salt) were synthesized, and their chemical formulas were finalized as [Zn(L1)Cl2]·5H2O·ZnCl2 (1), [Zn(L1)2Cl2]·4H2O·2CH3OH (2), [Zn(L2)Cl2]·3H2O·CH3OH (3), and [Zn(L2)2Cl2] (4). The synthesized complexes are water soluble, making them good candidates for biological applications. All four complexes have been characterized by elemental analysis and 1H NMR, IR, and UV-Vis spectroscopy. The IR stretching frequency of N=N and C=N bonds of complexes 1–4 have shifted to lower frequencies in comparison with free ligands, and a bathochromic shift was observed in UV-Vis spectra of all four complexes. The binding studies of ligands and complexes 1–4 with bovine serum albumin (BSA) resulted binding constants (Kb) of 3.09 × 104 M−1, 12.30 × 104 M−1, and 16.84 × 104 M−1 for ferene, complex 1, and complex 2, respectively, indicating potent serum distribution via albumins

Synthesis, Characterization, and Biological Studies of a Piperidinyl Appended Dipicolylamine Ligand and Its Rhenium Tricarbonyl Complex as Potential Therapeutic Agents for Human Breast Cancer

A novel ligand bearing a central piperidinyl sulfonamide group, N(SO2pip)dpa, and its corresponding Re tricarbonyl complex, [Re(CO)3(N(SO2pip)dpa)]+, have been synthesized in good yield. The methylene CH2 signal seen as a singlet (4.54 ppm) in a 1H NMR spectrum of the ligand in DMSO-d6 appears as two doublets (5.39, 5.01 ppm) in a spectrum of the [Re(CO)3(N(SO2pip)dpa)]+ complex and confirms the presence of magnetically nonequivalent protons upon coordination to Re. Structural results revealed that the Re–N bond lengths fall within the normal range establishing coordination of ligand to metal. The presence of intraligand π→π⁎ and n→π⁎ transitions is indicated by the absorption peaks around 200–250 nm in UV-visible spectra. Absorption peaks in UV-visible spectra around 300 nm for metal complexes were identified as MLCT transitions. The S–N stretch observed as a strong peak at 923 cm−1 for N(SO2pip)dpa appeared at a shorter frequency, at 830 cm−1 in an FTIR spectrum of the [Re(CO)3(N(SO2pip)dpa)]+. The intense fluorescence displayed by the N(SO2pip)dpa ligand has quenched upon coordination to Re. Relatively low IC50 values given by human breast cancer cells, MCF-7, (N(SO2pip)dpa = 139 μM, [Re(CO)3(N(SO2pip)dpa)]+ = 360 μM) indicate that N(SO2pip)dpa and [Re(CO)3(N(SO2pip)dpa)]+ are promising novel compounds that can be further investigated on their usage as potential anticancer agents