ABSTRACT
A pulmonary tuberculosis mouse model was used to assess the pharmacodynamic and pharmacokinetic characteristics of tuberculosis therapeutics. While membrane transporters play important roles in drug disposition and physiological homeostasis, their expressional changes and contribution have never been analysed in a tuberculosis animal model. The mRNA expression level of 20 Abc family transporters and 32 Slc family transporters in tuberculosis-infected mice were compared with those in naïve uninfected mice using real-time polymerase chain reaction (PCR). Mycobacterium tuberculosis infection induced many dramatic expression changes of families of both Abc transporters and Slc transporters at 4 and 8 weeks, as observed in the livers, kidneys, and intestines of test mice--and in a different mode, in the lungs and spleens as well. These changes were dependent on the tuberculosis progression with the tissue-specific manner, that is, in the lungs, the number of transporters of which the expression level changed due to M. tuberculosis infection had increased, and the magnitude of change also greater at 8 weeks, while in the spleen, the transcription of most transporters except Mrps had not changed or had recovered back to the same level of naïve transcription at 8 weeks. Understanding the expression changes of transporters will assist in setting up rational preclinical dosing plans through the ability to predict the pharmacokinetics of new anti-tuberculosis chemotherapeutics and, furthermore, will assist in the design of safer and more efficient drug regimens.
Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Anion Transport Proteins/biosynthesis , Cytokines/metabolism , Mycobacterium tuberculosis , RNA, Messenger/biosynthesis , Tuberculosis, Pulmonary/metabolism , Animals , Disease Models, Animal , Female , Mice , Mice, Inbred C57BL , Tuberculosis, Pulmonary/microbiologyABSTRACT
Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feist's acid 1 was condensed with purine derivatives by the SN2 type reaction. All the synthesized compounds were evaluated for antiviral activity.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Methane/analogs & derivatives , Purine Nucleosides/chemical synthesis , Purine Nucleosides/pharmacology , Hydrocarbons , Methane/chemistry , Microbial Sensitivity TestsABSTRACT
Novel exomethylene cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5 was synthesized in 4 steps, from Feists acid 1 and was condensed with purine derivatives by the SN2 type reaction to give some cyclopropyl nucleosides. The synthesized nucleosides did not showed any significant antiviral activity against HSV-1, HSV-2, HCMV, HIV-1, HIV-2, and HBV up to 100 microM.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclopropanes/chemical synthesis , Nucleosides/chemical synthesis , Cyclopropanes/pharmacology , Microbial Sensitivity Tests , Nucleosides/pharmacology , Viruses/drug effectsABSTRACT
Derivatives of elema-1,3-diene were synthesized in several steps as polar analogs of beta-elemene, antitumor agent under clinical phase. The lactone ring of compound 1 was opened by LiAlH4 to give diol 2 which was selectively protected by TBDPSCl. After acetylation of the secondary alcohol, the acetylated product was ozonolyzed and reduced to give elemane derivative 4 which was converted to diolefin 8 via selenides subsequent deprotection by tetrabutylammonium fluoride gave two compounds 9, 10.
