Search

14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3aand 3bshowed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3aand 3bdemonstrated significant brain penetration when dosed orally in mice. 3bshowed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3bwarrants future development. [ABSTRACT FROM AUTHOR]

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b(TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivoMIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3bhas emerged as a promising antitumor agent that shows excellent in vivoefficacy and is currently being evaluated in the clinic. [ABSTRACT FROM AUTHOR]

The study reports the frequency and clinical presentation of respiratory syncytial virus (RSV), human metapneumovirus, influenza (Inf V), parainfluenza, adenovirus (Adv), Chlamydia spp. and Mycoplasma pneumoniae in children with acute respiratory infections (ARI) in Rasht, Iran. Nasopharyngeal aspirates and swabs were collected from 261 children in 2003 and 2004. Pathogens were detected using polymerase chain reaction (PCR) and reverse transcription-PCR (RT-PCR), confirmed with sequence analysis. Ninety-three pathogens were detected in 83 children. RSV was present in 39 (15%), Adv in 37 (14%), Inf A in 11 (4%), C. trachomatis in 4 (2%) and M. pneumoniae, in 2 (1%) children. Neither parainfluenza nor metapneumovirus were detected. RSV, Inf A and C. trachomatis were more frequent in children with lower respiratory infections. Adv presented more frequently as upper respiratory infection. All pathogens, except M. pneumoniae, were detected in children with severe pneumonia. Viruses play a significant role in Iranian children with community-acquired ARI. [ABSTRACT FROM AUTHOR]