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PubMed2005

Effects of alkyl gallates on P-glycoprotein function.

In this study, we examined the effects of the food antioxidants, alkyl gallates, on the function of P-glycoprotein (P-gp) and elucidated the importance of alkyl chains and gallic acid moieties on the activity of P-gp. We examined the effects of three alkyl (n-butyl, n-octyl and n-dodecyl) gallates and their related compounds on the cellular accumulation and efflux of rhodamine 123 and daunorubicin in P-gp overexpressing KB-C2 cells. Alkyl gallates increased the cellular accumulation of these P-gp substrates dependent on their alkyl chain lengths by inhibiting the efflux of the substrates. n-Dodecylresorcinol also increased the accumulation, but its effect was less than that of n-dodecyl gallate. However, either lauric acid or n-dodecyl-beta-d-maltoside, which does not have a phenol group, did not increase the accumulation. The results indicated that both the gallic acid moiety and a long alkyl chain play important roles in the modification of P-gp function. The cytotoxicity of daunorubicin was recovered in the presence of alkyl gallates possibly due to their inhibition of P-gp function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

On the capillary gas chromatographic separation of enantiomers of N-trifluoroacetyl-O-alkyl esters of selected amino acids on 2,3-di-O-pentyl-6-O-acyl cyclodextrins.

In this work, the separation of enantiomers of N-TFA-O-alkyl amino acids on the 2,3-di-O-pentyl-6-O-acyl alpha-, beta- and gamma-cyclodextrin stationary phases has been studied. The influence of structure differences in the alkyl substituents bonded to the stereogenic carbon atom (R1), as well as in the ester group (R2) of the selected amino acid derivatives, and the selectivity of modified alpha-, beta- and gamma-cyclodextrin phases in gas chromatographic separation of derivatized amino acid enantiomers was studied in detail. A model set of N-TFA-alkyl esters of four amino acids was separated on five columns. The separation of enantiomers was evaluated in terms of the interactions of the alkyl substituents bonded to the stereogenic carbon (R1) and/or the ester group (R2) of the N-TFA-O-alkyl amino acid derivatives as well as the nature of the 3-O-acyl group in the 2,6-di-O-pentyl-3-O-acyl alpha-, beta- and gamma-cyclodextrins. It was shown that the variation in the enantiomeric separation with temperature and the retention order of enantiomers on a given cyclodextrin capillary column depends both on the nature of the bonded R1 and R2 alkyl groups. It was found that the temperature dependencies of selectivity factors, ln alpha on 1/T, were mostly non-linear. The thermodynamic data [delta(deltaS) and [delta(deltaH)] which characterize the chiral recognition were used to gain more insight into the mechanistic aspects of enantio separation of the N-TFA-O-alkyl amino acid derivatives on 2,6-di-O-pentyl-3-O-acyl-alpha-, beta- and gamma-cyclodextrins.

Amino Acids↗
PubMed1998

Protective actions of 5'-n-alkylated curcumins on living cells suffering from oxidative stress.

To elucidate the roles of 5'-n-alkyl chains of curcumin derivatives in their protective actions on cells against oxidative stress, we compared the efficacy of curcumin and 5'-alkylated curcumins to inhibit the peroxidation of linoleic acid and to protect rat thymocytes suffering from H2O2-induced oxidative stress with their permeation into cells. The inhibitory action of 5'-n-alkylated curcumins on lipid peroxidation increased as the length of hydrocarbon chains of 5'-n-alkylated curcumins was prolonged. This potency order was not confirmed for the protective actions of 5'-n-alkylated curcumins on cells against oxidative stress. Among 5'-alkylated curcumins, the most potent protective action was observed for 5'-n-C3H7-curcumin because it had the greatest permeation into the cells. Further increases in the length of hydrocarbon chains (up to n-C19H39) of 5'-n-alkylated curcumins greatly attenuated their protective actions by reducing their permeation into the cells.

Animals↗
PubMed1999

Alkyl nitrates as achiral and chiral solute probes in gas chromatography. Novel properties of a beta-cyclodextrin derivative and characterization of its enantioselective forces.

Achiral and chiral interactions of alkyl nitrates (R-O-NO2) with heptakis-(3-O-acetyl-2,6-di-O-pentyl)-beta-cyclodextrin (LIPODEX-D) in the gas phase were investigated chromatographically. Two major outcomes can be summarized. First, LIPODEX-D shows very fast temperature-dependent variations of the selectivity up to changes in the order of elution for C1-C5 alkyl nitrates. These changes in selectivity reveal that LIPODEX-D possesses different shape selectivities for small alkyl nitrates at different temperatures (40-80 degrees C), i.e. with increasing isothermal separation temperature extended (chain-like) alkyl nitrates have increased retention relative to bulky alkyl nitrates. The observations are highly reproducible and might indicate conformational changes of the cyclodextrin, however, an ultimate proof would require further spectroscopic investigation. Secondly, the chiral separations of systematically varied sets of C4-C11 alkyl nitrates allowed the thermodynamic characterization of enantiodiscriminating interactions. Quantitative evidence is provided showing that the presence of an ethyl group at the asymmetric carbon atom of an n-alkyl nitrate gives a strong enthalpic contribution to the resulting enantioselectivity. The Gibbs free energy differences -deltaR,S(deltaG) decrease systematically three to six times if the ethyl group is either shortened or enlarged by only a -CH2-increment. The results are based on two separate thermodynamic approaches, i.e. the determination of thermodynamic quantities (-deltaR,S(deltaG), -deltaR,S(deltaH), -deltaR,S(deltaS), Tiso) and a theoretical concept of enthalpy-entropy compensation. The data from our laboratory experiments also indicate that van der Waals interactions are responsible for chiral discrimination.

Chromatography, Gas↗
PubMed1997

Combination of the new minor groove alkylator tallimustine and melphalan.

The benzoyl nitrogen mustard derivative of distamycin A, tallimustine, belongs to a new class of alkylating agents, known as DNA minor groove alkylating agents. It alkylates adenine N3 with high sequence specificity, causing no alkylation of guanine N7, the main site of alkylation of clinically used nitrogen mustards such as L-PAM. The present study investigated the in vivo antitumour activity of a combination of tallimustine and melphalan (L-PAM). Two murine tumours were used: i.p. (intraperitoneally) transplanted L1210 leukaemia and i.m. (intramuscularly) transplanted M5076 ovarian reticulum cell sarcoma (M5). In L1210, which is only marginally sensitive to tallimustine, the combination of tallimustine 3 mg/kg i.p. with L-PAM 10 mg/kg i.p. was as effective as 20 mg/kg L-PAM, which is the maximum tolerated dose. In M5, which is sensitive to both drugs, the combination was superior to either drug alone. The results suggest that the combination of tallimustine and L-PAM--or possibly in general, minor groove alkylators and major groove alkylators--may be therapeutically advantageous and therefore should be investigated clinically.

Animals↗
PubMed1999

Occurrence of lysophosphatidic acid and its alkyl ether-linked analog in rat brain and comparison of their biological activities toward cultured neural cells.

Rat brain was found to contain substantial amounts of potent bioactive lipids lysophosphatidic acid (acyl LPA) (3.73 nmol/g tissue) and lysoplasmanic acid (alkyl LPA) (0.44 nmol/g tissue). The presence of alkyl LPA was confirmed by mild alkaline hydrolysis analysis and by gas chromatography/mass spectrometry analysis of the trimethylsilyl derivative. This is the first clear evidence of the occurrence of an alkyl LPA in nature. The predominant molecular species of acyl LPA are 18:1-, 18:0- and 16:0-containing species (46. 9, 22.5 and 18.8%, respectively). A significant amount of a 20:4-containing species (7.2%) was also detected in the acyl LPA fraction. We also confirmed that rat brain alkyl LPA consists of 16:0-, 18:0- and 18:1-containing species. Noticeably, either acyl or alkyl LPA is capable of stimulating neuroblastomaxglioma hybrid NG108-15 cells to elicit a Ca(2+) transient, the potencies being almost the same. Both acyl and alkyl LPAs also induce cell rounding upon addition to the cells. These results suggest that acyl and alkyl LPAs play important physiological roles as intercellular signaling molecules as well as the roles as metabolic intermediates in the nervous system.

Animals↗
PubMed2002

S-alkylation and S-amination of methyl thioethers--derivatives of closo-[B(12)H(12)](2-). synthesis of a boronated phosphonate, gem-bisphosphonates, and dodecaborane-ortho-carborane oligomers.

A variety of S-alkylated products was prepared by alkylation of methyl thioethers [MeSB(12)H(11)](2-) (5), [1-(MeS)-2(7,12)-(Me(2)S)B(12)H(10)](-) (6-8), and [1,2(7,12)-(MeS)(2)B(12)H(10)](2-) (9-11) with alkyl halides and tosylates in acetonitrile. Since these methyl thioethers can be prepared easily in B-10-enriched form on a large scale and due to their chemical versatility, they are potentially very attractive boron entities for the design and synthesis of therapeutics for boron neutron capture therapy of cancer. It was found that alkylation of 6-8 can be complicated by an equilibrium which establishes between, on the one hand, one of the former species and, on the other hand, 1,2(7,12)-(Me(2)S)(2)B(12)H(10) (2-4) and [1,2(7,12)-(MeS)(2)B(12)H(10)](2-) (9-11). A boronated phosphonate 1-(MeS(CH(2))(4)P(O)(OEt)(2))-7-(Me(2)S)B(12)H(10) (14g) and a gem-bisphosphonate 1-(MeS(CH(2))(3)CH[P(O)(OEt)(2)](2))-7-(Me(2)S)B(12)H(10) (14h) were prepared from thioether 7 and the corresponding iodide and tosylate, respectively, and subsequently converted to their sodium salts. The propargyl sulfonium salts obtained by alkylation of thioethers 7, 8, 10, and 11 with propargyl bromide have been further converted to two- and three-cage oligomers containing both ortho-carborane and dodecaborane moieties. Methyl thioethers derived from closo-[B(12)H(12)](2-) are excellent participants in Michael addition reactions in the presence of a strong acid. The sulfonium salts with tertiary alkyl and vinyl substituents have been prepared by this method. Methyl thioethers 5-11 react with hydroxylamine-O-sulfonate yielding the corresponding aminosulfonium salts, albeit in lower yields as compared to those in the alkylation reactions. Several derivatives of methyl thioethers 5-11 have been characterized by single-crystal X-ray diffraction.

Journal Article↗
PubMed2003

The influence of short strong hydrogen bonding on the structure and the physicochemical properties of alkyl-N-iminodiacetic acids in solid state and aqueous systems.

Alkyl-N-iminodiacetic acids with varying alkyl chain lengths have been prepared and characterized with respect to structure, acidic properties, and ability to form aggregates in water. The alkyl-N-iminodiacetic acids are the group of ligands with the lowest molecule weight which can be characterized as chelating surfactants, compounds with surface chemical properties which at the same time have a high ability to bind metal ions. The solid alkyl-N-iminodiacetic acids have a unique structure with neutral zwitterionic units linked together to polymer chains through a short strong hydrogen bond, d(O(-H)...O) approximately 2.46 A, and where the nu(O-H) stretching vibration at ca. 720 cm(-1) supports the presence of such a hydrogen bond. The polymer chains are cross-linked together to bilayers through relatively strong hydrogen bonds between ammonium and carboxylate groups, and where the parallel alkyl groups are interdigitating each other; the bilayer surface consists of hydrophilic iminodiacetic acid groups. The acidic properties of monomeric alkyl-N-iminodiacetic acids in water are in the expected ranges with pK(a) values of about 1.7, 2.3, and 10.3. n-Octadecyl-N-iminodiacetic acid, present as aggregates in water, displays very acidic properties of the first proton, and a substantially weakened acidity of the second proton, pK(a2) = 5.5-7.5, depending on ionic strength, and pK(a3) = 9.5-10.5. This pattern of the acidic constants strongly indicates that the polymer structure with short strong hydrogen bonds is maintained in the aggregates and that such bonds can exist in aqueous systems if they are supported by a strong and rigid backbone structure, as the bilayers of well-organized long interdigitating alkyl chains in the studied systems. Hydrogenbis(methyl-N-iminodiacetic acid) perchlorate precipitates from perchloric acidic solutions of methyl-N-iminodiacetic acid. The structure is built up of dimers of zwitterionic methyl-N-iminodiacetic acid units linked together by an extra proton in a short strong hydrogen bond, d(O(-H)...O) approximately 2.456(6) A, and nu(O-H) = 789 cm(-1).

Journal Article↗
PubMed2002

Alkylation of dihydrofullerenes.

The fulleride dianions C(60)(2-) and C(70)(2-) were generated by deprotonation of the corresponding hydrogenated fullerenes, 1,2-C(60)H(2) and 1,2-C(70)H(2). These anions were prepared in the presence of a variety of alkylating agents, and mono- or dialkylated products were obtained. Alkylation was not successful with sulfonate ester alkylating agents. Deprotonation of monoalkylated compounds, followed by second alkylation with a different alkylating agent, produced heterodialkylated compounds. The monoalkyated material was invariably the 1,2-isomers, while the dialkylated materials were generally 1,4-isomers, although some 1,2-isomer was observed in the C(70) context. The major product from alkylation of C(70)(2-) was the 7,23-isomer 13a, a structure where the alkylation took place near the equator of the fullerene cage, rather than at the more strained carbons near the poles.

Journal Article↗
PubMed2003

Photolysis of alpha-azidoacetophenones: direct detection of triplet alkyl nitrenes in solution.

We report the first detection of triplet alkyl nitrenes in fluid solution by laser flash photolysis of alpha-azido acetophenone derivatives, 1. Alphazides 1 contain an intramolecular triplet sensitizer, which ensures formation of the triplet alkyl nitrene by bypassing the singlet nitrene intermediate. At room temperature, azides 1 cleave to form benzoyl and methyl azide radicals in competition with triplet energy transfer to form triplet alkyl nitrene. The major photoproduct 3 arises from interception of the triplet alkyl nitrene with benzoyl radicals. The triplet alkyl nitrene intermediates are also trapped with molecular oxygen to yield the corresponding 2-nitrophenylethanone. Laser flash photolysis of 1 reveals that the triplet alkyl nitrenes have absorption around 300 nm. The triplet alkyl nitrenes were further characterized by obtaining their UV and IR spectra in argon matrices. (13)C and (15)N isotope labeling studies allowed us to characterize the C-N stretch of the nitrene intermediate at 1201 cm(-)(1).

Journal Article↗
PubMed1996

Synthesis and Properties of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI) Alkylation Subunit: Magnitude of Electronic Effects on the Functional Reactivity.

The synthesis of 7-methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI), a substituted CBI derivative bearing a C7 methoxy group para to the C4 carbonyl, is described in efforts that establish the magnitude of potential electronic effects on the chemical and functional reactivity of the agents. The core structure of the MCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors (15 and 20) followed by 5-exo-trig aryl radical-alkene cyclization (24 --> 25, 32 --> 33) for completion of the synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation of 28 for introduction of the activated cyclopropane. Two approaches to the implementation of the key 5-exo-trig free radical cyclization are detailed with the former proceeding with closure of 24 to provide 25 in which the required product functionalization was introduced prior to cyclization and the latter with Tempo trap of the cyclization product of the unfunctionalized alkene substrate 32 to provide 33. The latter concise approach provided the MCBI subunit and its immediate precursor in 12-13 steps in superb overall conversions (27-30%). Resolution of an immediate MCBI precursor and its incorporation into both enantiomers of 39-46, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-MCBI (29) revealed that introduction of the C7 methoxy group accelerates the rate of solvolysis by only 1.2-1.06x. This remarkably modest effect is inconsistent with C4 carbonyl protonation as the slow and rate-determining step of solvolysis or acid-catalyzed nucleophilic addition but is consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction. This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. For the natural enantiomers, this unusually small electronic effect on functional reactivity had little or no perceptible effect on their DNA alkylation selectivity, efficiency, and relative rates or on their biological properties. Perceptible effects of the C7 methoxy substituent on the unnatural enantiomers were observed and they proved to be 4-40x more effective than the corresponding CBI-based unnatural enantiomers and comparable in cytotoxic potency with the MCBI natural enantiomers. This effect is most consistently rationalized not by a C7 methoxy substituent effect on functional reactivity but rather through introduction of additional stabilizing noncovalent interactions which increase the unnatural enantiomer DNA alkylation efficiency and further stabilize its inherently reversible DNA alkylation reaction.

Journal Article↗
PubMed1999

A Novel, One-Pot Reductive Alkylation of Amines by S-Ethyl Thioesters Mediated by Triethylsilane and Sodium Triacetoxyborohydride in the Presence of Palladium on Carbon.

The reductive alkylation of primary amines with aldehydes or ketones is an important tool in the synthesis of wide variety of amines. We described here a novel, one-pot reductive alkylation method using multifunctional S-ethyl thioesters as a source for in situ generation of aldehydes to alkylate a range of multifunctional primary amines. The corresponding multifunctional secondary amines were obtained in good to excellent yields (mostly >90%). This one-pot reductive alkylation included the treatment of a mixture of protected S-ethyl thioester, primary amine, 10% Pd/C, and sodium triacetoxyborohydride in N,N-dimethylformamide with triethylsilane for 30 min at temperature lower than 20 degrees C. This method has special merit when the aldehyde is not stable enough to allow isolation and therefore does not lend itself to a stepwise strategy of reductive alkylation. This was the case with tert-butyl 1(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-oxobutyrate (10) which could not be obtained from the alpha-tert-butyl gamma-S-ethyl (S)-N-(9-fluorenylmethoxycarbonyl) thioglutamate (9). However, by our one-pot reductive alkylating method, treatment of 9-fluorenemethyl phenylalaninate (6a) with 9 afforded tert-butyl 2(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-[[3-phenyl-1(S)-(9-fluorenylmethoxycarbonyl)propyl]amino]butyrate (11) in 76% yield. Furthermore, the acid labile tert-butyloxycarbonyl, and the hydogenation labile benzyloxycarbonyl and benzyl protecting groups, were stable in the one-pot reductive alkylation reaction. While the conjugated double bond is stable in these reaction conditions, the monosubstituted C-C double bond, as in the allyl protecting group in alpha-allyl beta-cyclohexyl aspartate, was reduced to the corresponding propyl ester.

Journal Article↗
PubMed2006

Photodegradation of polyfluorene and fluorene oligomers with alkyl and aromatic disubstitutions.

The stability of fluorene-based compounds and polymers, especially at the bridged C-9 position under photoirradiation and thermal treatment, has claimed wide attention. We report the electronic, vibrational, and MALDI-TOF mass spectral combined studies for the fluorene oligomers with alkyl and aromatic substitutions under UV-light irradiation. The low-energy emission and the formation of ketonic defects after degradation highly depend on the proportion of alkyl substitution. The oligomer with fully aromatic substitution shows good stability, but when the proportion of alkyl substitution increases, their photostability rapidly decreases. The mass spectra show not only the mass of the fluorenone-fluorene trimer but also another new degradation product with a large mass (pristine oligomer plus 14) from alkyl oxidation, which testify to the assistance of alkyl side chain during degradation. We propose that the degradation of fluorene is a radical chain process propagated by alkyl side chains, and then the different stability between alkyl and aromatic substitution can be well explained.

Fluorenes↗
PubMed1999

Interleukin-2 causes an increase in saturated/monounsaturated phosphatidic acid derived from 1,2-diacylglycerol and 1-O-alkyl-2-acylglycerol.

Phosphatidic acid generation through activation of diacylglycerol kinase alpha has been implicated in interleukin-2-dependent T-lymphocyte proliferation. To investigate this lipid signaling in more detail, we characterized the molecular structures of the diradylglycerols and phosphatidic acids in the murine CTLL-2 T-cell line under both basal and stimulated conditions. In resting cells, 1,2-diacylglycerol and 1-O-alkyl-2-acylglycerol subtypes represented 44 and 55% of total diradylglycerol, respectively, and both showed a highly saturated profile containing primarily 16:0 and 18:1 fatty acids. 1-O-Alk-1'-enyl-2-acylglycerol represented 1-2% of total diradylglycerol. Interleukin-2 stimulation did not alter the molecular species profiles, however, it did selectively reduce total 1-O-alkyl-2-acylglycerol by over 50% at 15 min while only causing a 10% drop in 1,2-diacylglycerol. When radiolabeled CTLL-2 cells were challenged with interleukin-2, no change in the cellular content of phosphatidylcholine nor phosphatidylethanolamine was observed thereby ruling out phospholipase C activity as the source of diradylglycerol. In addition, interleukin-2 failed to stimulate de novo synthesis of diradylglycerol. Structural analysis revealed approximately equal amounts of 1,2-diacyl phosphatidic acid and 1-O-alkyl-2-acyl phosphatidic acid under resting conditions, both containing only saturated and monounsaturated fatty acids. After acute (2 and 15 min) interleukin-2 stimulation the total phosphatidic acid mass increased, almost entirely through the formation of 1-O-alkyl-2-acyl species. In vitro assays revealed that both 1,2-diacylglycerol and 1-O-alkyl-2-acylglycerol were substrates for 1,2-diacylglycerol kinase alpha, the major isoform in CTLL-2 cells, and that the lipid kinase activity was almost totally inhibited by R59949. In conclusion, this investigation shows that, in CTLL-2 cells, 1,2-diacylglycerol kinase alpha specifically phosphorylates a pre-existing pool of 1-O-alkyl-2-acylglycerol to form the intracellular messenger 1-O-alkyl-2-acyl phosphatidic acid.

Animals↗
PubMed2006

Rat butyrylcholinesterase-catalysed hydrolysis of N-alkyl homologues of benzoylcholine.

The purpose of this work was to study the catalytic properties of rat butyrylcholinesterase with benzoylcholine (BzCh) and N-alkyl derivatives of BzCh (BCHn) as substrates. Complex hysteretic behaviour was observed in the approach to steady-state kinetics for each ester. Hysteresis consisted of a long lag phase with damped oscillation. The presence of a long lag phase, with no oscillations, in substrate hydrolysis by rat butyrylcholinesterase was also observed with N-methylindoxyl acetate as substrate. Hysteretic behaviour was explained by the existence of two interconvertible butyrylcholinesterase forms in slow equilibrium, while just one of them is catalytically active. The damped oscillations were explained by the existence of different substrate conformational states and/or aggregates (micelles) in slow equilibrium. Different substrate conformational states were confirmed by 1H-NMR. The K(m) values for substrates decreased as the length of the alkyl chain increased. High affinity of the enzyme for the longest alkyl chain length substrates was explained by multiple hydrophobic interactions of the alkyl chain with amino acid residues lining the active site gorge. Molecular modelling studies supported this interpretation; docking energy decreased as the length of the alkyl chain increased. The long-chain substrates had reduced k(cat) values. Docking studies showed that long-chain substrates were not optimally oriented in the active site for catalysis, thus explaining the slow rate of hydrolysis. The hydrolytic rate of BCH12 and longer alkyl chain esters vs. substrate concentration showed a premature plateau far below V(max). This was due to the loss of substrate availability. The best substrates for rat butyrylcholinesterase were short alkyl homologues, BzCh - BCH4.

Animals↗
PubMed2005

Alkyl gallates, intensifiers of beta-lactam susceptibility in methicillin-resistant Staphylococcus aureus.

We found that ethyl gallate purified from a dried pod of tara (Caesalpinia spinosa) intensified beta-lactam susceptibility in methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus (MRSA and MSSA strains, respectively). This compound and several known alkyl gallates were tested with MRSA and MSSA strains to gain new insights into their structural functions in relation to antimicrobial and beta-lactam susceptibility-intensifying activities. The maximum activity of alkyl gallates against MRSA and MSSA strains occurred at 1-nonyl and 1-decyl gallate, with an MIC at which 90% of the isolates tested were inhibited of 15.6 microg/ml. At concentrations lower than the MIC, alkyl gallates synergistically elevated the susceptibility of MRSA and MSSA strains to beta-lactam antibiotics. Such a synergistic activity of the alkyl gallates appears to be specific for beta-lactam antibiotics, because no significant changes were observed in the MICs of other classes of antibiotics examined in this study. The length of the alkyl chain was also associated with the modifying activity of the alkyl gallates, and the optimum length was C5 to C6. The present work clearly demonstrates that the length of the alkyl chain has a key role in the elevation of susceptibility to beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed1993

Alkylating agents and immunotoxins exert synergistic cytotoxic activity against ovarian cancer cells. Mechanism of action.

Alkylating agents can be administered in high dosage to patients with ovarian cancer using autologous bone marrow support, but drug-resistant tumor cells can still persist. Immunotoxins provide reagents that might eliminate drug resistant cells. In the present study, concurrent treatment with alkylators and immunotoxins proved superior to treatment with each agent alone. Toxin immunoconjugates prepared from different monoclonal antibodies and recombinant ricin A chain (rRTA) inhibited clonogenic growth of ovarian cancer cell lines in limiting dilution assays. When alkylating agents and toxin conjugates were used in combination, the addition of the immunotoxins to cisplatin, or to cisplatin and thiotepa, produced synergistic cytotoxic activity against the OVCA 432 and OVCAR III cell lines. Studies performed to clarify the mechanism of action showed that cisplatin and thiotepa had no influence on internalization and binding of the 317G5-rRTA immunotoxin. Intracellular uptake of [195m]Pt-cisplatin was not affected by the immunoconjugate and thiotepa. The combination of the 317G5-rRTA and thiotepa, as well as 317G5-rRTA alone, increased [195m]Pt cisplatin-DNA adduct levels. The immunotoxin alone and in combination with the alkylators decreased intracellular glutathione levels and reduced glutathione-S-transferase activity. Repair of DNA damage induced by the combination of alkylators and 317G5-rRTA was significantly reduced when compared to repair after damage with alkylators alone. These findings suggest that immunotoxins affect levels and activity of enzymes required for the prevention and repair of alkylator damage.

Antibodies, Monoclonal↗
PubMed1989

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids.

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.

4-Quinolones↗