Nickel-Metformin Ternary Complexes: Geometrical, Thermal, DNA Binding, and Molecular Docking Studies.

Novel three nickel(II) complexes of type [Ni(metf)(o-phen)2]Cl2 (1), [Ni(metf)(opda)2]Cl2 (2), [Ni(metf)(2-2'bipy)2]Cl2 (3), (Metf = metformin, o-phen = ortho-phenanthroline, opda = ortho-phenylenediamine, 2-2' bipy = 2-2' bipyridyl) were synthesized and characterized by various analytical and spectral techniques. Based on these studies, octahedral geometry is assigned to these complexes. The DNA binding properties of these complexes were investigated by absorption, emission, and viscosity studies. From the spectral data, it was concluded that the complexes bind to DNA through groove mode of binding. The intrinsic binding constants (Kb) from absorption spectroscopy were 1.60 × 104, 3.57 × 104, and 5.70 × 104 M-1 for 1, 2, and 3, respectively, and Stern-Volmer quenching constants (Ksv) from emission spectroscopy were 0.11, 0.87, and 0.24, respectively. Thermal degradation pattern of the compounds was studied and Coats-Redfern method is used to determine kinetic parameters for complexes 1, 2, and 3 from thermal studies. The software Discovery Studio 2.1 was used to assess the binding affinity and interaction pattern of complexes with the B-DNA receptor protein and complex 1 has the highest dock score.

A2B- and A3-Type Boron(III)Subchlorins Derived from meso-Diethoxycarbonyltripyrrane: Synthesis and Photophysical Exploration.

The first direct fabrication of A2B- and A3-type B(III)subchlorins from meso-ethoxycarbonyl-substituted tripyrrane has been realized by condensation with appropriate acid chlorides (benzoyl chloride, butyryl chloride, and ethyl chlorooxoacetate). The aliphatic acid chloride-based annulation reaction is new to subporphyrinoid chemistry. The phenyl (6a)- or n-propyl (6b)-substituted derivatives could be oxidized to the corresponding B(III)subporphyrins upon refluxing with DDQ, whereas the triethoxycarbonyl moiety (6c) was found to be resistant to oxidation and exhibits the most red-shifted absorption (587 nm) and emission (604 nm). The study indicates that absorption and emission behaviors of the B(III)subchlorin can be tuned by the introduction of electron-rich or electron-deficient substituents at the meso-position. B(III)subchlorins 6a and 6c generate singlet oxygen efficiently (44 and 40%, respectively) and, thus, may find application as potential photosensitizers in photodynamic therapy (PDT).

1,2-Phenylene-Incorporated Smallest Expanded Calix[4]pyrrole via One-Step Synthesis of Tetrapyrrane: A Fluorescent Host for Fluoride Ion.

Synthesis of tetrapyrrane 8 from acetone and pyrrole via one-step condensation was achieved for the first time along with a much-improved yield of the tripyrrane 9. Diborylation of the tetrapyrrane and subsequent "1 + 1" cyclocoupling with 1,2-diiodobenzene following the Suzuki protocol generated novel o-phenylene incorporated macrocycle belonging to the smallest meso-expanded calix[4]pyrrole family. The latter macrocycle displays exclusive turn-on fluorescence sensing of fluoride ion upon complexation via a unique partial cone conformation supported by DFT analysis in acetonitrile solvent.

Antihypertensive activity of diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate: A continuation study in L-NAME treated wistar rats.

In the present study, we report that neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) relaxes the superior mesenteric artery in a concentration dependent manner (pD2 value 5.392 ±â€¯0.04; n = 8 for endothelium intact and 5.204 ±â€¯0.03; n = 8 for endothelium denuded mesenteric rings, respectively). The relaxation response of neolignan1 was found to be endothelium independent and sensitive to 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-on (ODQ; 1 µM) and tetraethyl ammonium (TEA; 1 mM). In-silico studies showed good LibDock score (92.66) of neolignan1 with BKCa channel and are in well corroboration with ex-vivo study. Further, neolignan1 significantly decreased the systolic blood pressure, diastolic blood pressure and mean arterial pressure in the Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 50 mg/kg) treated Wistar rats at the dose of 30 and 100 mg/kg given once orally for 15 days. In addition, neolignan1 is well tolerated up to 100 mg/kg when given as a repeated dose, once orally for 28 days in Swiss albino mice. Neolignan1 was well absorbed from oral route, reached peak at 4 h and eliminated below detection level by 12 h after administration. Our present study concludes that neolignan1 produced relaxation in superior mesenteric artery by opening of BKCa channel and produced significant antihypertensive activity in L-NAME treated Wistar rats and was well tolerated by the experimental animal.

Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate exhibits antihypertensive activity in rats through increase in intracellular cGMP level and blockade of calcium channels.

We report here the antihypertensive and vasorelaxant potential of some steroidal and non-steroidal compounds identified through a library of compounds. All the novel analogues showed vasorelaxant potential in isolated rat aorta. The most potent lead neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) produced concentration dependent relaxation with [pD2 5.16±0.05; n=16 and Emax 96.97%±1.12%; n=16]. The neolignan1 relaxation is independent of endothelium and is sensitive to ODQ (1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one; a blocker of soluble guanylyl cyclase (sGC) which synthesizes cGMP (cyclic guanosine monophosphate)). ELISA analysis of treated arterial tissues showed concentration-dependent increase in cGMP level in treated tissues compared to control (2.03 and 7.16 fold of control at 10 and 30µM of neolignan1, respectively) and a synergistic increase in cGMP level by 26.66 fold compared to control when used in combination with sildenafil (10µM; a known inducer of cGMP level by selectively blocking cGMP specific phosphodiesterase 5). Our present study reports for the first time that neolignans produce relaxation in isolated rat aorta through increase in intracellular cGMP level. The ODQ resistant relaxation of neolignan1 is mediated by blockade of voltage dependent L-type calcium channel (VDCC) as observed in the experiment with CaCl2. Neolignan1 upon intravenous administration via tail vein in Spontaneously Hypertensive Rats (SHR) produced significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). The present study concludes that neolignan1 exhibited antihypertensive potential in rats through rise in intracellular cGMP and blockade of VDCC.

ß-Hexaalkylporphycenes: Positional Effect of Alkyl Groups toward Design and Control of Structural and Photophysical Properties in Isomeric Hexaethylporphycenes.

Two novel ß-hexaalkylated porphycenes, i.e., 2,3,7,12,13,17- (HOT) and 2,3,6,12,13,16-hexaethylporphycenes (HIT) were introduced for the first time in porphycene chemistry. These were synthesized through McMurry coupling reactions of new isomeric unsymmetrically substituted triethylbipyrrole dialdehydes. The positional effects of alkyl groups could be manifested through significant alteration in structure of porphycene cores and, as a consequence their photophysical properties, not noticed in ß-octaethylporphycene. HOT displays significant fluorescence accompanied by reasonable singlet oxygen generation ability.

Recent Advances in chemistry and pharmacology of 2-methoxyestradiol: An anticancer investigational drug.

2-Methoxyestradiol (2ME2), an estrogen hormone metabolite is a potential cancer chemotherapeutic agent. Presently, it is an investigational drug under various phases of clinical trials alone or in combination therapy. Its anticancer activity has been attributed to its antitubulin, antiangiogenic, pro-apoptotic and ROS induction properties. This anticancer drug candidate has been explored extensively in last twenty years for its detailed chemistry and pharmacology. Present review is an update of its chemistry and biological activity. It also extends an assessment of potential of 2ME2 and its analogues as possible anticancer drug in future.

Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics, and binding free energy calculations.

Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the ß-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the ß-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in ß-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of ß-tubulin and prevent its dynamics, leading to a better packing between α and ß subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (-113.655 kJ/mol) had better binding compared to Cmp19 (-95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers.

Hexaethylsubporphyrins: ß-alkyl analogues in the subporphyrin family.

Two new subporphyrins were synthesized for the first time from a ß-substituted pyrrole i.e. 3,4-diethylpyrrole via pyridine-tri-N-(3,4-diethylpyrrolyl)borane as building blocks. These ß-hexaethylsubporphyrins are true contracted congeners of ß-octaethylporphyrin (OEP). While the meso-triphenyl derivative of hexaethylsubporphyrin could be synthesized by following the reported method, the meso-free analogue could only be synthesized by condensation with trioxane, in the presence of catalytic methanesulfonic acid. These contracted macrocycles display interesting absorption, and emission behaviour including substituent dependent S2 fluorescence owing to the presence of flexible electron donating ethyl groups at their ß-positions. The optical response and ultrafast S2 state dynamics of these systems suggest that it may be possible to tune the properties of the subporphyrin to develop efficient systems for solar energy capture and conversion processes.

ß,ß'-Bipyrrole Fusion-Driven cis-Bimetallic Complexation in Isomeric Porphyrin.

An unprecedented cis-bimetallic complex of dinaphthoporphycene (DNP), namely [Pd2(µ-DNP)(µ-OAc)2], is reported. The most striking feature of this complex is that two palladiums coordinate to the macrocycle on the same side and are closely held together (Pd-Pd: 2.67 Å) by two bridging acetate ligands exhibiting significant metal-metal bonding interaction (bond order 0.18 evaluated by NBO analysis). Interestingly, replacing acetate with acetylacetonate (acac) could stabilize an unusual mono-palladium complex of DNP, where Pd coordinates unsymmetrically to two ring Ns above the macrocyclic plane, as well as coordinating with two Os of the acac ligand. Remarkably, the rigid DNP core displays enhanced complexation induced aromaticity (as per NICS and HOMA analysis), despite undergoing severe core deformation during complexation with metal ion(s) as noticed from their solid-state structures.

Calix[4]pyrroles with Shortest Possible Strap: Exclusively Selective toward Fluoride Ion.

Four new calix[4]pyrroles with the shortest possible strap so far through ortho-linking of the aromatic unit have been synthesized, including a naphthalene-derived fluorescent receptor. They show exclusive selectivity toward the fluoride ion as confirmed by (1)H NMR, isothermal titration calorimetry, and fluorescence spectroscopic study. Anion affinity could also be modulated further via functionalization at the strap. Computational analysis displays calix[4]pyrroles binding to fluoride ion in a very unusual 1,3-alternate conformation where the anion resides on the opposite side of the strap.

Current status on development of steroids as anticancer agents.

Steroids are important biodynamic agents. Their affinities for various nuclear receptors have been an interesting feature to utilize them for drug development particularly for receptor mediated diseases. Steroid biochemistry and its crucial role in human physiology, has attained importance among the researchers. Recent years have seen an extensive focus on modification of steroids. The rational modifications of perhydrocyclopentanophenanthrene nucleus of steroids have yielded several important anticancer lead molecules. Exemestane, SR16157, fulvestrant and 2-methoxyestradiol are some of the successful leads emerged on steroidal pharmacophores. The present review is an update on some of the steroidal leads obtained during past 25 years. Various steroid based enzyme inhibitors, antiestrogens, cytotoxic conjugates and steroidal cytotoxic molecules of natural as well as synthetic origin have been highlighted. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".

Colorimetric sensing of fluoride ion by new expanded calix[4]pyrrole through anion-π interaction.

Three new expanded calix[4]pyrroles were synthesized, where the two dialkylldipyrromethane units are linked via C-C double bonds. One of them, calix[2]bispyrrolylethene, colorimetrically senses fluoride ion only, owing to anion-π interaction in polar aprotic solvents.

Meso-diacylated calix[4]pyrrole: structural diversities and enhanced binding towards dihydrogenphosphate ion.

Meso-diacylated calix[4]pyrrole was obtained via acid catalysed condensation of meso-acylated dipyrromethane with acetone. Selective presence of flexible substituents at the calix[4]pyrrole periphery led to interesting structural motifs in the solid state along with enhanced binding towards anions, especially dihydrogenphosphate ion via anchoring.