PurposeThe purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.MethodsDerivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).ResultsCarbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.ConclusionThe activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.
The role of micelles and organic solvents as the modifiers of the aqueous mobile phase in reversed-phase liquid chromatography (RPLC) in controlling retention and selectivity is discussed. Elution strength increases in RPLC with an increase in organic solvent or micelle concentration. Simultaneous enhancement of separation selectivity with elution strength in the hybrid eluents of water-organic solvent-micelles was observed. This selectivity enhancement occurs systematically, i.e. peak separation increases monotonically with volume fraction of organic solvent added to micellar eluent, and is observed for a large number of ionic and nonionic compounds with different functional groups and for two surfactants (anionic and cationic). For two test mixtures, 13 amino acids/peptides and 15 phenols, it is shown that a better separation and shorter analysis time are observed at stronger hybrid eluents. This selectivity enhancement can be attributed to the competing partitioning equilibria in micellar LC systems and/or to the unique characteristics of micelles to compartmentalize solutes and organic solvents.
4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.
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