ABSTRACT
We present a setup of optical tweezers combined with linear and nonlinear microspectroscopies that enhances the capabilities of capture and analysis of both techniques. We can use either a continuous-wave (cw) Ti:sapphire laser for Raman measurements or a pulsed femtosecond Ti:sapphire laser that permitted the observation of nonlinear results such as hyper-Raman, hyper-Rayleigh, and two-photon luminescence. Only the high peak intensity of the femtosecond laser allows the observation of all these nonlinear spectroscopies. The sensitivity of our system also permitted the observation of morphology-dependent resonance (MDR) modes of a single stained trapped microsphere of 6 microm. The possibility of performing spectroscopy in a living microorganism optically trapped in any desired neighborhood would mean that one can dynamically observe the chemical reactions and/or mechanical properties changing in real time.
ABSTRACT
The near-infrared (NIR) laser Raman trapping system was applied to study liquid-liquid extraction in a single droplet in a subpicoliter range. The system trapped a single subpicoliter toluene droplet in water using the NIR laser beam and provided time-dependent optical images of the droplet during liquid-liquid extraction. The size of the trapped droplet gradually increased afterp-nonylphenol solution was added in water. The Raman spectra of the droplet prove that the increase of the droplet size was caused by the absorption of p-nonylphenol from the water. The distribution coefficient of p-nonylphenol in the sub-picoliter droplet was much higher than that in bulk solution.
ABSTRACT
In order to study structure-activity relationships, a series of new non-steroidal progesterone receptor ligands based on PF1092A was synthesized with structural modifications (mostly introduction or removal of a methyl group) at the 3-, 4-, 5-, 7- or 9-position in the 6-acetoxy-4a, 5, 6, 7-tetrahydro-3, 4a, 5-trimethylnaphtho[2,3-b]furan-2(4H)-one skeleton. Critical positions for high binding affinity to the progesterone receptor were identified.
Subject(s)
Ligands , Receptors, Progesterone/chemistry , Sesquiterpenes , Furans/chemical synthesis , Kinetics , Naphthols/chemical synthesis , Penicillium/chemistry , Structure-Activity RelationshipABSTRACT
Five novel 3-hydroxyl derivatives of sixteen-membered macrolide possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar moiety were synthesized by using a combination of structurally stable silyl acetal protection and selective hydrogenolysis of a 3"-methylthiomethyl ether to a 3"-OMe group. Several derivatives having n-butyryl, i-butyryl and n-valeryl substituent at the 4"-OH group exhibited significant antibacterial activity in vitro. One of them, 4"-O-n-butyryl-3"-O-methylleucomycin V, showed improved therapeutic effect in mice.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Hexoses/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Hexoses/chemistry , Macrolides , Mice , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Six derivatives of sixteen-membered macrolides possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar were synthesized via 3"-methylthiomethyl ether intermediates in reasonable yield. Introduction of a methyl group on the 3"-hydroxyl group of midecamycin A1 was effective for enhancing its antibacterial activity. All these derivatives exhibited excellent therapeutic effects in mice, and some of them showed improved pharmacokinetics compared with the natural antibiotics (mycarose type) in mice. Facile synthesis of 9-O-acylated analogues are also described.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Hexoses/chemistry , Hexoses/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Hexoses/chemical synthesis , Macrolides , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred ICR , Molecular Structure , Pneumococcal Infections/drug therapy , Staphylococcal Infections/drug therapyABSTRACT
The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as a neutral sugar are described. These potent novel derivatives have been efficiently synthesized avoiding glycosylations. Two hydroxyl groups in mycarose of the tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated. Sequential deprotections of silyl groups afforded 4-O-alkyl-L-cladinose analogues and 3,4-di-O-alkyl-L-mycarose analogues of leucomycin V. Some 4-O-alkyl-L-cladinose analogues exhibited potent antibacterial activities. The most active derivative, 3"-O-methyl-4"-O-(3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro and extremely high concentrations in serum after oral administrations in mice and in hamsters.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Hexoses/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Cricetinae , Female , Hexoses/pharmacokinetics , Hexoses/pharmacology , Macrolides , Male , Mesocricetus , Mice , Mice, Inbred ICR , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as the neutral sugar are described. The nine novel derivatives have been synthesized by glycosylation with 1-thio sugars. The most active derivative of them showed prolonged antibacterial activity in rat plasma in vitro and improved pharmacokinetics.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Hexoses/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Glycosylation , Leucomycins/blood , Leucomycins/urine , Male , Mice , Microbial Sensitivity Tests , Rats , Structure-Activity RelationshipABSTRACT
The synthetic oligosaccharide moiety of the antibiotic calicheamicin and the head-to-head dimer of this oligosaccharide are known to bind to the minor groove of DNA in a sequence-selective manner preferring distinct target sequences. We tested these carbohydrates for their ability to interfere with transcription factor function. The oligosaccharides inhibit binding of transcription factors to DNA in a sequence-selective manner, probably by inducing a conformational change in DNA structure. They also interfere with transcription by polymerase II in vitro. The effective concentrations of the oligosaccharides for inhibition of transcription factor binding and for transcriptional inhibition are in the micromolar range. The dimer is a significantly more active inhibitor than is the monomer.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemistry , DNA/metabolism , Oligosaccharides/metabolism , Transcription Factors/metabolism , Transcription, Genetic/drug effects , Base Sequence , Carbohydrate Sequence , DNA Polymerase II/drug effects , DNA-Binding Proteins/metabolism , Enediynes , Molecular Conformation , Molecular Sequence Data , Oligodeoxyribonucleotides/metabolism , Oligosaccharides/pharmacology , Protein Binding/drug effects , STAT3 Transcription Factor , Trans-Activators/metabolismABSTRACT
The preparation and antitumor effects of 3'-deamino-3'-morpholino derivatives of pirarubicin are described. Di-N-alkylation of pirarubicin with bis(2-iodoethyl)ether gave 3'-morpholino-pirarubicin, which was converted into its 13-tosylhydrazone, 13-deoxy derivative and 13-(S)- and 13-(R)-dihydro derivatives. Intraperitoneal administration to murine tumors indicated that the effective dose ranges of the compounds having sp3 carbon at C-13 position were broader than those of the compounds having sp2 carbon. By oral administration, 13-(S)-dihydro isomer was more effective than 13-(R)-dihydro isomer.
Subject(s)
Doxorubicin/analogs & derivatives , Leukemia L1210/drug therapy , Morpholines/chemistry , Administration, Oral , Animals , Chromatography, Thin Layer , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Female , Injections, Intraperitoneal , Leukemia P388 , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Morpholines/administration & dosage , Tumor Cells, CulturedABSTRACT
The preparation and biological evaluation of N-salicylidene derivatives of pirarubicin are described. Pirarubicin was treated with various kinds of aryl aldehydes. Most of compounds synthesized here were more active than pirarubicin in vitro. Some of them showed significant prolongation of the survival period in experimental mice by oral administration. Interestingly, a derivative containing forphenicine exhibited the broadest dose-response range by intraperitoneal administration.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Doxorubicin/analogs & derivatives , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Leukemia, Experimental/drug therapy , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/chemical synthesis , Chemical Phenomena , Chemistry , Chromatography, Thin Layer , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/chemical synthesis , Doxorubicin/therapeutic use , Female , Mice , Molecular Structure , Tumor Cells, CulturedABSTRACT
It was reported that doxorubicin inhibited virus reverse transcriptase. We have synthesized various new 14-O-acyladriamycins. The derivatives having a 17-O-benzoyl group with hydrophobic aliphatic side chains showed stronger inhibitory activity on human immunodeficiency virus reverse transcriptase and lower cytotoxicity on mouse leukemia cells.