Refinement of the crystal structure of (RS)-carnitine hydrochloride

A single crystal of (RS)-carnitine hydrochloride has been obtained, and its crystal structure has been refined by an x-ray structural experiment.Tashkent Pharmaceutical Institute. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 842–844, November–December, 1991.     

Refinement of the crystal structure of (RS)-carnitine hydrochloride

A single crystal of (RS)-carnitine hydrochloride has been obtained, and its crystal structure has been refined by an x-ray structural experiment.     

Synthesis and in vitro evaluation of imidazole-based wakayin analogues

Analogues of wakayin based on diimidazo[1,5,4-de, 1,5,4-h]-quinoxaline have been prepared and evaluated with respect to cytostatic and cytotoxic activity. Assays in a 60-cell-line human cancer panel revealed selective activity against cells with the VEGF (Flt-1) receptor.     

Design of a cyclopropyl quinone methide reductive alkylating agent. 2

A cyclopropyl quinone methide is formed by elimination of a leaving group from an appropriately functionalized hydroquinone. The presence of a carbon spacer results in the formation of a fused ring rather than the classic methide species. Discussed herein is cyclopropyl quinone methide formation from a pyrido[1,2-a]indole ring system. Both nucleophilic and electrophilic attack on the fused cyclopropane ring results in pyrido[1,2-a]indole and azepino[1,2-a]indole products. The stereoelectronic effect plays less a role in the relatively flexible pyrido[1,2-a]indole system compared to its role in the pyrrolo[1,2-a]-indole system. A 13C label on the fused cyclopropane ring permitted the rapid identification of complex rearrangement products observed in this study.     

Solution kinetics of CC-1065 A-ring opening: substituent effects and general acid/base catalysis

pH-rate studies were carried out on 2-substituted derivatives of the CC 1065 A-ring over the range of pH 5 to 0. The goals were to document the presence of general-acid-catalyzed cyclopropyl ring opening near neutrality and to assess the role of the 2-substituent on the rate of nucleophile trapping by the cyclopropyl ring. Our studies show that the cyclopropyl group undergoes reversible general-acid/base-catalyzed trapping of chloride nucleophiles above pH 4. This finding implies that the general-acid-catalyzed alkylation of DNA minor groove by the A-ring is feasible. pH-rate studies also showed that the 2-substituent does not influence the pKa of the protonated carbonyl of the A-ring (pKa approximately 1) and has relatively little effect on the rate of nucleophile trapping. This finding is consistent with calculations that show the fused pyrrolo ring as the source of carbonyl oxygen electron density. The 2-nitrogen, on the other hand, only releases electrons to the carbonyl of the 2-substituent and does not greatly influence trapping of nucleophiles by the A-ring cyclopropyl group.     

Fatigue crack propagation in PVC: Effects of molecular weight and specimen history

In this study, an earlier investigation of the effects of molecular weight on fatigue crack propagation, FCP, in PVC was extended and earlier tentative conclusions were verified using samples whose molecular weight distributions were relatively constant and narrow. In the range of M_w between 6 × 10⁴ and 2 × 10⁵, a strong effect of M on the FCP rate per cycle (da/dN) as a function of the range in the stress intensity factor (δ K) was observed. While the apparent fracture toughness increased moderately with M, FCP rates at constant δK decreased by three orders of magnitude over the range examined. This strong dependence, which followed the empirical relationship da/dN = A e^B/M δKⁿ, implies that cyclic disentanglement is more difficult the higher M. Preliminary observations were also made on the roles of sample orientation, mean stress and thermal history. It was found that the residual orientation that survived specimen fabrication had a slight but significant effect on FCP rates and the maximum values of δ K obtainable prior to fracture (δK _max). Thus the smaller the angle between the loading and orientation directions, the lower da/dN and the higher δK_max; the magnitude of the effect was greater, the lower the value of M. The mean stress also affected the FCP rate, sometimes positively and sometimes negatively, depending on the material. In contrast, little effect of prior thermal history of the FCP rate was noted. Just as an increase in temperature to above T _g is known to erase the effects of aging, so did cyclic loading, a t least in this case.     

Chemistry of pyrrolo[1,2-a]indole- and pyrido[1,2-a]indole-based quinone methides. Mechanistic explanations for differences in cytostatic/cytotoxic properties

In the present study we investigate pyrido[1,2-a]indole- and pyrrolo[1,2-a]indole-based quinones capable of forming quinone methide and vinyl quinone species upon reduction and leaving group elimination. Our goals were to determine the influence of the 6-membered pyrido and the 5-membered pyrrolo fused rings on quinone methide and vinyl quinone formation and fate as well as on cytostatic and cytotoxic activity. We used the technique of Spectral Global Fitting to study the fleeting quinone methide intermediate directly. Conclusions regarding quinone methide reactivity are that carbonyl O-protonation is required for nucleophile trapping and that the pKa value of this protonated species is near neutrality. The abnormally high protonated carbonyl pKa values are due to the formation of an aromatic carbocation species upon protonation. The fused pyrido ring promotes quinone methide and vinyl quinone formation but slows nucleophile trapping compared to the fused pyrrolo ring. These findings are explained by the presence of axial hydrogen atoms in the fused pyrido ring resulting in more steric congestion compared to the relatively flat fused pyrrolo ring. Consequently, pyrrolo[1,2-a]indole-based quinones exhibit more cytostatic activity than the pyrido[1,2-a]indole analogues due to their greater nucleophile trapping capability.