Biomedical subjects
Publications and source records attributed to S I Kang.
A new steroidal alkaloid, 12-O-nicotinoylsarcostin, gagamine (1), was isolated from the roots of Cynanchum caudatum Max. (Asclepiadaceae), together with a known alkaloid, gagaminine (2). Their structures were established using spectroscopic methods, some 13C-NMR data of 2 have to be revised.
The 8-alkyl- (3-6), 8-phenyl- (7), 12-bromo- (8), 8-alkyl-12-bromo- (9-12), and 12-bromo-8-phenyl- (13) berberine derivatives were prepared and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Introduction of the alkyl or phenyl group and the bromine atom into the C-8 and C-12 positions of berberine (1), respectively, led to significant increases of the antimicrobial activity. In both the 8-alkyl- and 8-alkyl-12-bromo-berberines (3-6 and 9-12, respectively), the antibacterial activity increased as the length of the aliphatic chain increased. The exception was the activity against Candida albicans and Escherichia coli, which did not always increase as the alkyl side chain lengthened. Among the compounds tested, 12-bromo-8-n-hexylberberine (12) was 64, 256, 128, 16, and 32 times more active against Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, E. coli, and C. albicans, respectively, in comparison to the clinically used berberine. Compound 12 was also found to be 8, 16, and 128 times more active against S. aureus, S. enteritidis, and C.albicans, respectively, than kanamycin sulfate, but was of the same order of activity against B. subtilis, and only one-fourth as active against E. coli.
13-Alkyl derivatives (2-6 and 8-12) of berberine (1) and palmatine (7) were subjected to in vitro antibacterial activity tests against Bacillus subtilis and Salmonella enteritidis. Antibacterial activity increased as the length of the C-13 aliphatic side chain increased. The effects of the oxygen-substituents on aromatic rings A, C, and D of protoberberinium salts 13-20 on the antimicrobial activity against Staphylococcus aureus, B. subtilis, S. enteritidis, Escherichia coli, and Candida albicans are also discussed. The change in lipophilicity of the protoberberinium salts caused by modification of the substituents appears to influence the antibacterial activity. 13-Hexylberberine (6) and 13-hexylpalmatine (12) exhibited the greatest antibacterial activity.
RATIONALE AND OBJECTIVES: The authors investigated the effect of multimerization on the relaxivity of macrocyclic gadolinium (Gd) chelates. The objective was to develop more sensitive magnetic resonance imaging (MRI) contrast agents to study biochemical processes. METHODS: Covalently linked nonionic, macrocyclic, multimeric lanthanide chelates that belong to the classes of dimers, trimers, tetramers, hexamer, and octamer, in the molecular weight range approximately 1 to 5 KDa, were synthesized. The chemical linkage was based on either the amide bond or the 2-hydroxypropylidene bond. Relaxivity values, 20r1, on Gd3+ chelates and hydration numbers, Q, on Tb3+ chelates were determined. RESULTS: Relaxivity values increased with molecular weight and Q values were not affected, the increase in r1 in attributable to the expected increase in the overall rotational correlation time, tau r with an increase in molecular weight. The rigidity of the linkers, which is expected to affect the intrachelate rotational correlation time tau r* that makes a contribution to the overall correlation time, tau r, exerted a noticeable effect. The hydroxyl-based chelates generally had lower r1 values than the amide-based chelates. This is rationalized as arising from the longer and thereby rate-limiting effect of the tau m value for the hydroxyl chelates compared with that reported of the amide-based chelates. This rate limiting effect of tau m becomes a dominant factor controlling attainable enhanced relaxivity when multimers based on traditional chelate designs are used for MRI applications. CONCLUSIONS: Approaches aimed at enhancing relaxivity by modulating the water relaxation time, tau m, will be important for the future development of functional MRI contrast agents for the imaging of biochemical processes.
Mastoparan is an amphiphilic tetradecapeptide derived from wasp venom which activates G-proteins. Several secondary effects have been attributed to this peptide, including activation of phospholipase and phosphatidylinositol kinase. The aim of the present study was to investigate the effects of mastoparan on vascular contractility. Rabbit aortic rings were cut and mounted on a force transducer to record isometric tension on a polygraph. The effects of mastoparan were then investigated on the contractile responses in the isolated rabbit aorta with or without endothelium. The results were summarized as follows; 1. Mastoparan caused biphasic response, a transient relaxation followed by a further contraction, in norepinephrine (NE)-precontracted ring with endothelium. These effects were not observed in the aorta in the absence of endothelium. 2. Mastoparan-induced transient relaxation was significantly inhibited by treatment with a N-omega-nitro-L-arginine or methylene blue. 3. When an inhibitor of phospholipase C, neomycin was added to the precontracted aortic ring with NE, the transient relaxation induced by mastoparan was inhibited, but sustained contraction was not inhibited. 4. When an inhibitor of phospholipase A2, quinacrine and inhibitor of the cyclooxygenase pathway, indomethacin, were added to a precontracted ring with NE, the transient relaxation induced by mastoparan was not inhibited, but sustained contraction was inhibited. 5. Mastoparan induced a contraction of the aorta either with or without endothelium. Indomethacin and nifedipine inhibited mastoparan-induced contraction. From the above results, we concluded that mastoparan acts on the endothelium and modifies the release of endothelium-derived relaxing factors such as nitric oxide and also endothelium-derived contracting factors such as metabolites of arachidonic acid.
A variety of organoselenium alkylating agents were synthesized, using 2-hydroxyethyl and 3-hydroxypropyl selenocyanate intermediates, and studied to determine their chemical reactivities with 4-(4-nitrobenzyl)pyridine (NBP) and cytotoxicities against CCRF-CEM, L1210/0, and L1210/L-PAM cells. The comparison between the 2-chloroethyl sulfides and selenides 1-4 revealed the markedly enhanced nucleophilicity of selenium (Se) over sulfur (S) by two or more orders of magnitude. This finding indicates that a major consideration in the design of antitumor alkylating organoselenides is the reactivity of selenium. A Taft plot of the experimental first-order rate constant, knbp, and sigma* in a series of 2-chloroethylseleno compounds gave a slope of -1.73 (rho*), with the exception of 2-chloroethyl 2-nitrophenyl selenide (10). The anomalous behavior of 10 is explained in terms of the ortho-nitro stabilization effect directly interacting with the selenium atom of ethyleneselenonium ion to form a 5-membered cyclic intermediate. In the same series, a 5000-fold difference in alkylating reactivity offered only a sixfold variation in cytotoxicity against CCRF-CEM cells. Increasing the alkylating chain length from ethlene to propylene units markedly reduced alkylating reactivities. In the CH3Se(CH2)n Cl series, 16 (n = 3) was 1.5 X 10(5) times slower than 2 (n = 2) in NBP alkylation, revealing that 3-chloro-n-propyl selenides are not chemically reactive enough to be biological alkylating agents despite the presence of the highly nucleophilic selenium atom. Replacement of chloride with mesylate in 3-substituted propyl selenides, such as 17 and 20, restored desirable reactivities and cytotoxicities.
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5-(2-Acylethynyl)-2,4-dimethoxypyrimidines (3-6) were synthesized in excellent yields from 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine (2) by treatment with acid chlorides in the presence of anhydrous aluminum chloride. Compounds 3-6 were deblocked with chlorotrimethylsilane and sodium iodide in acetonitrile to the corresponding 5-[(2-acyl-1-iodo)vinyl]uracils (7-10), which on treatment with potassium hydroxide in dioxane yielded the corresponding 5-(2-acylethynyl)uracils (11-14). The 5-(2-acylethynyl)uracils were found to be active against Ehrlich ascites carcinoma (EAC) cells in vivo, the most active compounds being 5-(2-benzoylethynyl)uracil (11) and 5-(2-p-toluoylethynyl)uracil (12). The T/C values of 281 and 300 were obtained for compounds 11 and 12, respectively, in the case of mice bearing EAC cells. The 5-(2-acylethynyl)uracils have also shown in vitro activity against CCRF-CEM and L1210/0 tumor cell lines. The lead compound 5-(2-p-toluoylethynyl)uracil effectively inhibited thymidylate synthetase.
Examples of a new class of alkylating agents, selenium mustards, were prepared for study of their chemical kinetic properties and cytotoxicities against human lymphoblastoid CCRF-CEM cells. In a series of para-substituted aryl 2-chloroethyl selenides, a linear free energy relationship between the first-order rate constant, k'nbp and sigma p gave a rho value of -1.3, indicating that formation of a cyclic ethylene selenonium ion is the rate-controlling step for alkylation of 4-(4-nitrobenzyl)pyridine (NBP). Consistent with the ethyleneselenonium ion pathway, rates of solvolyses were extremely sensitive to increasing water content, and a positive correlation was found between reactivity with NBP and nucleophilic selectivity (Swain-Scott s constant). The s constant, which predicts for variation in intracellular product spread, varied from 0.53 up to 0.95, equal to aliphatic nitrogen mustards. Alkylating activities based on extent of NBP alkylation, however, showed relatively low values, 8-23% of that of mechlorethamine, possibly due to hydrolysis occurring by a separate pathway from nucleophilic substitution. Reactivities and nucleophilic selectivities both showed positive correlations with cytotoxicities, suggesting that the rate and extent of alkylation of relatively strong nucleophilic centers mediate the biologic effects of these compounds. Two bifunctional selenium mustards were substantially more cytotoxic than monofunctional aromatic selenides. No additional cytotoxicity due to the selenium atom was observed, with the exception of diselenide (-SeSe-) compounds. Thus, selenium alkylating agents kinetically and biologically resemble classical, mustard-type alkylating agents.