Structure‐cytotoxicity relationship for apoptotic inducers organotin(IV) derivatives of mandelic acid and L‐proline and their mixed ligand complexes having enhanced cytotoxicity

Structure‐cytotoxicity relationship of di?/tri‐organotin(IV) derivatives of mandelic acid ( 1 – 4 ), L‐proline ( 5 – 7, 15, 16 ), and mixed ligand complexes of latter with 1,10‐phenanthroline ( 8 – 14 ) investigated on the basis of MTT assay against human cancer cell lines, viz. MCF‐7 (mammary cancer), HepG2 (liver cancer) and PC‐3 (prostate cancer) in vitro indicated that all complexes except methyl‐ and octyl‐ analogues displayed potential cytotoxicity. The most active one is dibutyltin(IV) mandelate ( 2 ) exhibiting IC₅₀ 2.03 ± 0.40, 0.98 ± 0.23 and 3.86 ± 1.68 μM against MCF‐7, HepG2 and PC‐3, respectively, which is ≈ 15 and 2.5 times against MCF‐7, 20 and 5 times against HepG2 and 5 and ≈ 3 times against PC‐3 more cytotoxic than cis‐platin and 5‐fluorouracil, respectively. Diorganotin(IV) derivatives of mandelic acid are more cytotoxic than triorganotin analogues. Organotin(IV) derivatives of L‐proline (except Bu₃Sn(Pro) 16 ) are less cytotoxic than those of mandelic acid but their cytotoxicity is enhanced by complexion with 1,10‐phenanthroline. This may be due to the structural planarity and extended π system of 1,10‐phenanthroline which facilitates their transportation across the cell membrane and enhances the possibility of DNA intercalation over the planar L‐proline ring, and eventually, their DNA binding affinity so as to interfere with the cellular functions of DNA leading to apoptosis. Various biophysical experiments such as DNA fragmentation, acridine orange and comet assays, and flow cytometry assay using annexin V–fluorescein isothiocyanate (FITC) and propidium iodide (PI) have been carried out in order to ascertain their mode of action. The observed results indicated that the major cause of cancer cell death is apoptosis, but a minor role played by necrosis cannot be excluded. It is concluded on the basis of the observed results that the nature and number of organic groups bonded to tin as well as the nature of counter anions play an important role in determining the cytotoxicity of organotin(IV) compounds.     

Unexpected reactivity of pyridinium salts toward alkynyl Fischer complexes to produce oxo‐heterocycles

The unprecedented reaction of ketone‐containing aromatic pyridinium salts 3a ‐ e and alkynyl Fischer complexes 1a ‐ f proceeds via a mild domino process to provide 4,6‐disubstituted pyran‐2‐ones 5a ‐ k and 2,3,5‐trisubstituted furans 6a ‐ h (45‐97%). According of the results of isotopic labeling experiments, a mechanism involving an initial Michael addition appears to be the key step, obtaining a mesomeric structure responsible for the formation of both products.     

Tin(IV) Schiff base complexes derived from pyridoxal: Synthesis,spectroscopic properties and cytotoxicity

The synthesis of monomeric pentacoordinated diorganotin(IV) complexes derived from pyridoxal hydrochloride and 4‐ or 5‐R ‐substituted ortho ‐aminophenols is described. The complexes were characterized using UV–visible, infrared, mass, ¹H NMR, ¹³C NMR and ¹¹⁹Sn NMR spectral techniques. The molecular structure of three complexes was established using X‐ray diffraction: 3b and 3d show a distorted trigonal bipyramidal geometry, in which the basal plane is defined by the butyl groups and the iminic nitrogen atom, whereas the oxygen atoms from the aromatic ring occupy axial positions; in contrast, complex 3e exhibits a square pyramidal geometry. The cytotoxic activity of all complexes against human cell lines U‐251 (glioblastoma), K‐562 (chronic myelogenous leukemia), HCT‐15 (human colorectal cancer), MCF‐7 (human breast cancer) and SKLU‐1 (non‐small‐cell lung cancer) was evaluated, and the inhibitory percentage values indicated higher activity than the reference standard, cisplatin. Acute toxicity studies were performed in vivo for the prepared complexes to determine the lethal medium dose (LD₅₀) after intraperitoneal administration to mice.     

Preparation and in vitro investigations of triphenyl[ω‐(tetrahydro‐2H‐pyran‐2‐yloxy)alkyl]tin(IV) compounds

The reaction of SnPh₃Li with X(CH₂)_n O–THP (THP = tetrahydro‐2H ‐pyran‐2‐yl; n  = 3, 4, 6, 8, 11; X = Cl, Br) afforded organotin(IV) compounds with the general formula Ph₃Sn(CH₂)_n O–THP ( 1 – 5 ). The tetraorganotin(IV) compounds were characterized using multinuclear NMR and infrared spectroscopies and high‐resolution mass spectrometry. Anticancer activity of the synthesized compounds was tested in vitro against the A2780 (ovarian), A549 (lung), HeLa (adenocarcinoma) and SW480 (colon) tumour cell lines with SRB assay. The in vitro investigations revealed that when a shorter chain was present a higher activity was achieved; however compounds 1 – 5 were found to be less active than cisplatin. In addition, the most active compound, 1 , enters A2780 cells and causes apoptosis by triggering both intrinsic and extrinsic caspase pathways.     

Spectroscopic and X‐ray structural characterization of new polymeric organotin(IV) carboxylates and their in vitro antifungal activities: Part II

The reactions of R₃SnCl (R = Me, Bu or Ph) with sodium 4‐phenylbutyrate, Na(OPh^b), in EtOH yielded three polymeric triorganotin carboxylates, namely [R₃Sn(OPh^b)]_n (R = Me ( 1 ), Bu ( 2 ) or Ph ( 3 )). All complexes were spectroscopically characterized using Fourier transform infrared, ¹¹⁹Sn Mössbauer, ¹H NMR, ¹³C{¹H} NMR and ¹¹⁹Sn{¹H} NMR spectral techniques. In addition, the crystal structures of 1 and 3 were determined using single‐crystal X‐ray diffraction. Their polymeric structures are sustained by bridging carboxylates which connect two five‐coordinate Sn(IV) centres. Each metallic cation displays a distorted trigonal bipyramidal coordination geometry (Addison's parameters ranging from 0.84 in 1 to 0.77–0.91 in 3 ), with the oxygen atoms occupying the apical positions and the organic groups at the equatorial corners. The one‐dimensional zigzag chains of 1 propagate along the b ‐axis, whereas 3 displays wave‐like double polymeric chains along the b ‐axis. For both 1 and 3 , parallel one‐dimensional polymeric chains are interconnected by C─H⋅⋅⋅π interactions. The antifungal activity of 1 – 3 was screened against Candida albicans (ATCC 18804), C. tropicalis (ATCC 750), C. glabrata (ATCC 90030), C. parapsilosis (ATCC 22019), C. lusitaniae (CBS 6936) and C. dubliniensis (clinical isolate 28). The antifungal activity of 3 was noteworthy since it was not only more active than 1 and 2 , but also more active than the control drugs (nystatin and fluconazole nitrate) in some cases.     

Facile Synthesis of Coumarinyl Isothiocyanate from Amino Coumarin

One-pot conversion of amino coumarin to corresponding coumarinyl isothiocyanate using carbon disulfide, iodine, and pyridine is described. In this reaction, pyridine acts as a solvent as well as a catalyst to give coumarinyl isothiocyanate. Excellent yield, short reaction time, and mild reaction conditions make this method a useful synthetic procedure for one-pot preparation of coumarinyl isothiocyanate.     

Favorski Type Rearrangement in the Lead Tetraacetate Oxidation of Cycloalkanones

The cycloalkanones (1a-lf) have been converted into their corresponding cycloalkane carboxylates (2a-2f) by a lead (IV) acetate promoted rearrangement in presence of perchloric acid in triethyl orthoformate.     

High‐molecular‐weight symmetrical multiblock copolymers: Synthesis by RAFT polymerization and characterization

High‐molecular‐weight (MW) symmetrical multiblock copolymers, based on the hydrophobic monomers styrene (Sty) and methyl methacrylate (MMA), and the more polar monomer, 2‐vinyl pyridine (2VPy), were prepared using stepwise reversible addition‐fragmentation chain transfer polymerization. All copolymers shared a common poly(ethylene glycol) (PEG) midblock, introduced as a bifunctional macromolecular chain transfer agent. In total, five ABA triblock copolymers, five ABCBA pentablock terpolymers, and two ABCDCBA heptablock quaterpolymers (comprising four different monomer types) were synthesized. The MWs of the multiblock polymers were determined using gel permeation chromatography (GPC) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, with the latter values being closer to the theoretically expected, whereas GPC MW distributions were relatively narrow, broadening with the number of blocks. The compositions of the synthesized polymers, as determined by ¹H NMR spectroscopy, were also close to the expected values. Finally, films cast from chloroform solutions of the pentablock terpolymers P2VPy‐b‐PSty‐b‐PEG‐b‐PSty‐b‐P2VPy, PSty‐b‐PMMA‐b‐PEG‐b‐PMMA‐b‐PSty, and P2VPy‐b‐PMMA‐b‐PEG‐b‐PMMA‐b‐P2VPy examined using transmission electron microscopy exhibited PSty and PMMA cylinders (first two) and lamellae (third terpolymer). © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4957–4965     

Stereoregular control of poly(4‐vinyl pyridine) on free radical polymerization by using the inclusion complex with randomly methylated β‐cyclodextrin

Highly heterotactic poly(4‐vinyl pyridine)s (P4VPs) with the fraction of mr content (f_mr) > 0.81 were synthesized by free radical polymerization of 4‐vinyl pyridine (4VP) with randomly methylated β‐cyclodextrin (β‐RMCD) in acidic aqueous media of HNO₃ and CF₃COOH at 40 °C. The heterotacticity of P4VP strongly depended on the neutralization of 4VP. The complete neutralization of 4VP with HNO₃ or CF₃COOH increased the heterotacticity of P4VP, whereas atactic P4VP was obtained in water. The partial decomposition of β‐RMCD by HCl reduced the heterotacticity of P4VP (f_mr ≈ 0.74). The structures of inclusion complexed monomers were determined by Job's plot, 2D NMR with nuclear Overhauser enhancement spectroscopy analyses, and simulation by MM2. The 1:2 complex with [β‐RMCD]:[4VP] with meso placement of 4VPs in β‐RMCD was formed when 4VP was completely neutralized with acid, whereas the 1:1 complex was formed in water. The mechanism of heterospecific control by using β‐RMCD was proposed. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012