ABSTRACT
A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Discovery/methods , Lung Neoplasms/enzymology , Oxamic Acid/analogs & derivatives , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Benzothiazoles/toxicity , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, SCID , Molecular Structure , Molecular Targeted Therapy , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Oxamic Acid/therapeutic use , Oxamic Acid/toxicity , Protein Binding , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Xenograft Model Antitumor AssaysABSTRACT
Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.
Subject(s)
CD4 Antigens/chemistry , CD4 Antigens/pharmacology , HIV Fusion Inhibitors/chemistry , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Animals , HIV Envelope Protein gp120/metabolism , HIV Fusion Inhibitors/pharmacokinetics , HIV Infections/drug therapy , Macaca mulatta , Molecular Docking Simulation , Oxamic Acid/analogs & derivatives , Oxamic Acid/chemistry , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , RatsABSTRACT
To date, several small molecules of CD4 mimics, which can suppress competitively the interaction between an HIV-1 envelope glycoprotein gp120 and a cellular surface protein CD4, have been reported as viral entry inhibitors. A lead compound 2 (YYA-021) with relatively high potency and low cytotoxicity has been identified previously by SAR studies. In the present study, the pharmacokinetics of the intravenous administration of compound 2 in rats and rhesus macaques is reported. The half-lives of compound 2 in blood in rats and rhesus macaques suggest that compound 2 shows wide tissue distribution and relatively high distribution volumes. A few hours after the injection, both plasma concentrations of compound 2 maintained micromolar levels, indicating it might have promise for intravenous administration when used combinatorially with anti-gp120 monoclonal antibodies.
Subject(s)
CD4 Antigens/chemistry , HIV Fusion Inhibitors/pharmacokinetics , Molecular Mimicry , Oxamic Acid/analogs & derivatives , Piperidines/pharmacokinetics , Administration, Intravenous , Adsorption , Animals , CD4 Antigens/metabolism , HIV Fusion Inhibitors/administration & dosage , HIV Fusion Inhibitors/chemistry , Half-Life , Macaca mulatta , Molecular Structure , Oxamic Acid/administration & dosage , Oxamic Acid/chemistry , Oxamic Acid/pharmacokinetics , Piperidines/administration & dosage , Piperidines/chemistry , Rats , Rats, Sprague-Dawley , Surface Properties , Tissue DistributionABSTRACT
Se usaron 3 plantas diuréticas. Determinar ácido oxálico en las diferentes drogas tanto crudas como cocidas en forma individual y combinado, usando los métodos de la ADAC. La edad de la planta, es determinante en el contenido de ácido oxálico. Las muestras crudas lanzaron mayor porcentaje de ácido oxálico. Se comprobó que existen algunos factores determinantes que influyen directa o indirectamente en la concentración de ácido oxálico en los vegetales.
