120289-22-7Relevant academic research and scientific papers
Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity
Greenwald, Richard B.,Pendri, Annapurna,Conover, Charles D.,Lee, Chyi,Choe, Yun H.,Gilbert, Carl,Martinez, Anthony,Xia, Jing,Wu, Dechun,Hsue, Mei-mann
, p. 551 - 562 (1998)
An improved synthesis of the hindered PEG-camptothecin diester transport form has been achieved using the Mukaiyama reagent. We have also assessed the effect of changing the electronic configuration of the (d-position of PEG-camptothecin transport forms on the rates of hydrolysis of the pro-moiety, and attempted to correlate these differences to efficacy in two animal models. In addition to the simple substitution of N for O, other synthetic modifications of these atoms were accomplished by employing heterobifunctional linker groups. The half lives by disappearance (rates of hydrolysis) of the transport forms in buffer and rat plasma were determined. It was established that anchimeric assistance to hydrolytic breakdown of the pro-moiety occurs in a predictable manner for some of these compounds. Results for the new derivatives in a P388 murine leukemic model and HT-29 human colorectal xenograft study are also presented. The use of a glycine linker group was found to provide similar efficacy in rodent models to that of simple camptothecin 20-PEG ester, and displayed enhanced pharmacokinetics. Copyright (C) 1998 Elsevier Science Ltd.
Luminescent magnetic hollow mesoporous silica nanotheranostics for camptothecin delivery and multimodal imaging
Sahu, Swagatika,Sinha, Niharika,Bhutia, Sujit K.,Majhi, Megharay,Mohapatra, Sasmita
, p. 3799 - 3808 (2014)
The synthesis of a novel and specific nanoplatform for anticancer drug delivery, fluorescence imaging and contrast agent in magnetic resonance imaging has been described. Hierarchical theranostic hollow magnetic mesoporous spherical particles with fluorescent carbon encapsulated within the mesoporous framework have been prepared by the hydrothermal carbonization approach. These particles show MR contrast behaviour by affecting the proton relaxation with transverse relaxivity (r2) of 150.05 mM-1 S-1. These multifunctional fluorescent magnetic nanoparticles have been conjugated with the hydrophobic drug, camptothecin, and a molecular marker, folic acid, using appropriate surface chemistry. The drug-conjugated hybrid nanoparticles inhibit cell growth through the induction of apoptosis as demonstrated in HeLa cells. This journal is the Partner Organisations 2014.
Discovery of Novel 2,8-Diazaspiro[4.5]decanes as Orally Active Glycoprotein IIb-IIIa Antagonists
Mehrotra, Mukund M.,Heath, Julie A.,Smyth, Mark S.,Pandey, Anjali,Rose, Jack W.,Seroogy, Joseph M.,Volkots, Deborah L.,Nannizzi-Alaimo, Lisa,Park, Gary L.,Lambing, Joseph L.,Hollenbach, Stanley J.,Scarborough, Robert M.
, p. 2037 - 2061 (2007/10/03)
In our efforts to develop orally active GPIIb-IIIa antagonists with improved pharmaceutical properties, we have utilized a novel 2,8-diazaspiro[4.5]decane scaffold as a template. We describe here our investigation of a variety of templates including spiropiperidinyl-γ -lactams, spiropiperidinylimide, spiropiperidinylureas, and spiropiperidinylhydantoins. With the appropriate acidic and basic pharmacophores in place, each template yielded analogues with potent GPIIb-IIIa inhibitory activity. One of the compounds, 59 (CT50787), was also used to demonstrate for the first time the use of a pharmacological agent which is αIIbβ3 specific to display biological activity in a lower species such as mouse and to extend bleeding times. Evaluation of the pharmacokinetic properties of selected compounds from each series in rat, dog, and cynomolgus monkey has led to the identification of 22 (CT51464), a double prodrug, with excellent pharmacokinetic properties. It exhibited good pharmacokinetic profile across species (F% = 33 (Cyno), 73 (dog), 22 (rat); t1/2β = 14. 2 h (Cyno), 8.97 h (dog), 1.81 h (rat)). The biologically active form, 23 (CT50728), displayed inhibition of platelet aggregation in platelet rich plasma (PRP) with an IC50 value of 53 nM in citrate buffer, 110 nM in PPACK anticoagulated PRP, and 4 nM in solid-phase GPIIb-IIIa competition binding assay (ELISA). Both 23 and 22 were stable in human liver microsomes, did not inhibit the P450 3A4 isozyme, and had low protein binding (18.22% for 23) and a desirable log P (0.45 ± 0.06 for 22, and -0.91 ± 0.32 for 23). It is predicted that the high oral bioavailability for these compounds in multiple species should translate into lower intra- and intersubject variability in man. The long plasma half-life of the lead is consistent with once or twice daily administration for chronic therapy. Analogue 22 (CT51464) thus appears to be a promising oral GPIIb-IIIa inhibitor with significantly improved pharmacokinetic properties over the previously described clinical candidates and may be found useful in the treatment of arterial occlusive disorders.
Biotransformation of amlodipine. Identification and synthesis of metabolites found in rat, dog and human urine / confirmation of structures by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry
Beresford,Macrae,Alker,Kobylecki
, p. 201 - 209 (2007/10/02)
Metabolism of the dihydropyridine calcium antagonist (R,S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5 methoxycarbonyl-6-methyl-1,4-dihydropyridine (amlodipine) has been studied in animals and man using 14C-labelled drug. The metabolite patterns are complex; 18 metabolites have been isolated from rat, dog and human urine. Based on chromatographic and mass-spectral evidence, structures have been proposed for the main metabolites and confirmed by synthesis of unambiguous reference compounds.
