Studies in polyphenol chemistry and bioactivity. 4.(1) Synthesis of trimeric,tetrameric, pentameric,and higher oligomeric epicatechin-derived procyanidins having all-4beta,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest

We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin 4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4beta,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.     

A molecular orbital study of the changing role ofd-orbitals in transition metal compounds: ZnS,FeS and CrS

SCF-MO studies as FeS, CrS and ZnS illustrate the changing role ofd-orbitals along a transition series, where they become at first good acceptors playing an important role in the bonding, then so stable that their electrons behave essentially as “core” electrons in agreement with the conjecture of Phillips and Williams [1].     

The Isolation,Structure, and Synthesis of Davana Ether,an Odoriferous Compound of the Oil of Artemisia pallens Wall.

Several stereoisomers of 2,6,10-trimethyl-2:5, 7:10-diepoxy-dodeca-3,5,11-triene ( 3 ) have been isolated from the oil of Artemisia pallens. The synthesis of the isomeric mixture is described.     

Using flow injection analysis to time-resolve rhythmic and pulsatile signals

Continuous monitoring can be used to detect rhythms, an important aspect of biology. But peaks of concentration are broadened by dispersion so that they overlap their neighbours and obscure high frequency chemoperiodicities. In this study, flow injection was found experimentally to be useful in resolving these. A rhythmically varying pattern of permanganate concentration was measured spectrophotometrically. The rhythm (frequency 0.08 Hz) was observable at a dispersion coefficient of 3.0 but not at 3.9 (when only a single peak was recorded). It was again observable using the same high dispersion manifold but positioned after an injection valve that subsampled the stream at intervals. A design based on this work is proposed for an automated instrument that outputs a time series of concentration measures.     

Synthetic thermally reversible gel systems. IV

The polymerization kinetics in water of acrylylglycinamide (AG) initiated by K₂S₂O₈ was studied over the temperature range 40.0 to 60.0°C. Monomer concentration was varied from 7.8 × 10^?3 to 31.2 × 10^?3M and catalyst from 1.85 × to 11.10 × 10^?5M. The rate expression is ?d[M]/dt = R_p, = k_1.22[K₂S₂O₈]^0.5[M]^1.22, and the overall empirical rate constant, k_1.22 = 1.14 × 10¹¹e^?15,800/RT 1.^0.72 mole^?0.72 min^?1. To explain the dependence on monomer, a kinetic scheme which includes a bimolecular reaction (k₂) between monomer and initiator is suggested. The simplified expression which describes the initial rate of polymerization is: ?d[M]/dt = R_p, = k₄(2[I]/k₅)^1/2[M](k₁ + k₂[M])^1/2, where k₁, k₂, k₄ and k₅ are rate constants for S₂O₈ = decomposition, a bimolecular reaction between monomer and initiator, propagation, and termination, respectively. Individual bimolecular rate constants are expressed in liter/mole-min. The equation predicts a dependence on monomer concentration between 1.0 and 1.5 with 1.5 being approached a t high monomer concentrations. Plots of R_P²/[M]² versus [M] are linear, as predicted by the postulated reaction route and values for k₂ and k₄/k₅^1/2 were obtained from the slopes and intercepts of these plots. The temperature dependence of the bimolecular monomer-initiator reaction is k₂ = 5.19 × 10²¹e^?36,000/RT. Instead of the usual behavior, the k₄/k₅^1/2 ratio was found to decrease with temperature and the difference of activation energies, (E₄ ? E₅/2), is ?1.50 kcal. The temperature dependence of the propagation to square root of the termination rate constant ratio is k₄/k₅^1/2 = 6.16e^1500/RT. These rather unusual results may be related to the ability of AG polymers in water to form thermally reversible gels; even above the gel melting points, the polymers are considerably aggregated in solution. This would tend to make the bimolecular termination reaction more temperature dependent and also account for the high values (59–69) for the k₄/k₅^1/2 ratios. For similar temperatures, the overall rate constants for AG are approximately four times those for acrylamide.     

Isocyanide addition to MN2(CO)5(Ph2PCH2PPh2)2 and the formation of a four-electron doubly-bridging isocyanide

The reactions of Fe(CO)₅, Fe(CO)₄P(C₆H₅)₃, M(CO)₆ (M  W, Mo, Cr), and (CH₃C₅H₄Mn(CO)₃ with KH and several boron and aluminium hydrides were investigated. Iron pentacarbonyl was converted quantitatively to K⁺Fe(CO)₄-(CHO) by hydride transfer from KBH(OCH₃)₃ allowing isolation of [P(C₆H₅)₃]₂-Nⁿ⁺Fe(CO)₄(CHO)^? in 50% yield. Lower yields were obtained with LiBH(C₂H₅)₃, and other hydride sources gave little or no formyl product. The stability of Fe(CO)₄(CHO)^? in THP was found to depend on the cation, decreasing in the order [P(C₆H₅)₃]₂N⁺ > K⁺ > Na⁺ > Li⁺. No formyl complexes were isolated and no spectroscopic evidence for formyl formation was observed in the reactions of the other transition metal carbonyls with several hydride sources. Fe(CO)₄-P(C₆H₅)₃ gave K₂Fe(CO)₄ when treated with KHB(OCH₃)₃. When treated with LiBH(C₂H₅)₃, W(CO)₆ gave a mixture of HW₂(CO)₁₀^?and (OC)₅W(COC₂H₅)^?; the latter was methylated to give the carbene complex (OC)₅WC(OCH₃)C₂H₅.     

Overtone spectroscopy of H2O clusters in the V(OH) = 2 manifold: infrared-ultraviolet vibrationally mediated dissociation studies

Spectroscopy and predissociation dynamics of (H2O)2 and Ar-H2O are investigated with vibrationally mediated dissociation (VMD) techniques, wherein upsilon(OH) = 2 overtones of the complexes are selectively prepared with direct infrared pumping, followed by 193 nm photolysis of the excited H2O molecules. As a function of relative laser timing, the photolysis breaks H2O into OH and H fragments either (i) directly inside the complex or (ii) after the complex undergoes vibrational predissociation, with the nascent quantum state distribution of the OH photofragment probed via laser-induced fluorescence. This capability provides the first rotationally resolved spectroscopic analysis of (H2O)2 in the first overtone region and vibrational predissociation dynamics of water dimer and Ar-water clusters. The sensitivity of the VMD approach permits several upsilon(OH) = 2 overtone bands to be observed, the spectroscopic assignment of which is discussed in the context of recent anharmonic theoretical calculations.     

The Synthesis and Reactions of Yomogi Alcohol. Conversion of the artemisyl skeleton to the santolinyl skeleton by a 1,2-shift of a vinyl group. Synthesis of santolinatriene

The synthesis of yomogi alcohol (2, 5, 5-trimethylhepta-3,6-dien-2-ol, 2 ) is described, and experiments directed towards its allylic rearrangement to artemisia alcohol detervatives have been carried out. Acidic reagents open the ring of yomogi alcohol epoxide ( 16 ) at with participation of the 6,7-double-bond, a shift of the vinyl group results to yield a compound with the santolinyl skeleton. The same reagents are without effect when this double bond reduced. Action of butyllithium of the benzaldehyde acetal ( 41 ) of 2, 5-dimethyl-4-vinyl-2, dihydroxy-hex-5-ene ( 28 ), obtained by acid-catalyzed ring opening of yomogi alcohol epoxide in the presence of benzaldehyde, leads to santolinatriene ( 42 ). This vinyl shift is not observed in the case of O-acetyl yomogi alcohol epoxide ( 46 ), from white a compound believed to be an oxetan 48 (R ? COCH₃) is formed with concomitent shift of the acetate group. Further unusual reactions of the oxetan are described, and some observation about the epoxidation of sterically hindered allyl alcohols and their acetates are made.     

Remarkable variations in the luminescence of frozen solutions of [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone). Structural and spectroscopic studies of the effects of anions and solvents on Gold(I) carbene complexes

The unusual luminescence behavior of the two-coordinate gold(I) carbene complex, [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone), is reported. Upon freezing in a liquid N(2) bath, the colorless, nonluminescent solutions of [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone) become intensely luminescent. Strikingly, the colors of the emission differ in different solvents and appear only after the solvent has frozen. Solid [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone) is also luminescent, and the luminescence is attributed to the formation of extended chains of gold(I) centers that are connected through aurophilic attractions. Crystallographic studies of [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone) and [Au[C(NHMe)(2)](2)](BF(4)), which is also luminescent, reveal that both involve extended chains of cations and that the anions are hydrogen bonded to the cations through cation N-H groups. However, these chains differ in the Au...Au separations in each and in the carbene ligand orientations. In contrast, [Au[C(NMe(2))(NHMe)](2)](PF(6)) forms a colorless, nonluminescent solid, and in that solid there are no Au...Au interactions, a factor which supports the contention that aggregated species are responsible for the luminescence of [Au[C(NHMe)(2)](2)](PF(6)) x 0.5(acetone) in the solid state and in frozen solutions.     

Voltammetric Reduction of alpha- and gamma-[S2W18O62]4- and alpha-, beta-, and gamma-[SiW12O40]4-: isomeric dependence of reversible potentials of polyoxometalate anions using data obtained by novel dissolution and conventional solution-phase processes

Comparative studies on the voltammetric reduction of the alpha and gamma isomers of Dawson [S(2)W(18)O(62)](4)(-) and alpha, beta, and gamma forms of Keggin [SiW(12)O(40)](4)(-) polyoxometalate anions have been undertaken. For the six reversible one-electron [S(2)W(18)O(62)](4)(-)(/5)(-)(/6)(-)(/7)(-)(/8)(-)(/9)(-)(/10)(-) processes in acetonitrile, reversible potentials (E(0)(')) were found to be independent of isomeric form within experimental error (+/-5 mV). However, because both the alpha and gamma* isomers of [Bu(4)N](4)[S(2)W(18)O(62)] are insoluble in water, solid-state voltammetric studies with microcrystals adhered to electrode surfaces in contact with aqueous Et(4)NCl and Bu(4)NCl electrolyte media were also possible. Although no isomeric distinction was again detected in the solid-state studies, it was found that reduction of adhered solid by four or more electron equivalents led to rapid dissolution. When Et(4)NCl was the electrolyte, this dissolution process coupled with potential cycling experiments enabled conventional solution-phase data to be obtained in water for the analogous six one-electron reduction steps previously detected in acetonitrile. A strong medium effect attributed to Lewis acidity effects was apparent upon comparison with E(0)(') data obtained in water and acetonitrile. In contrast, with the [SiW(12)O(40)](4)(-) system, E(0)(') values for the [SiW(12)O(40)](4)(-)(/5)(-)(/6)(-)(/7)(-) processes in acetonitrile exhibited a larger (about 70 mV) dependence on isomeric form, and the isomerization step, [gamma-SiW(12)O(40)](6)(-)--> [alpha-SiW(12)O(40)](6)(-), was detected on the voltammetric time scale. The influence of isomeric form on reversible potential data is considered in terms of structural and charge density differences exhibited in the [S(2)W(18)O(62)](4)(-) and [SiW(12)O(40)](4)(-) systems studied in this paper and published data available on the alpha, beta, gamma, and gamma isomers of [As(2)W(18)O(62)](6)(-) and [P(2)W(18)O(62)](6)(-) Dawson anions and Keggin systems.