458 Comparative pharmacokinetics and intermediary metabolism of of 4-demethyl-4- cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN)

A Rational for Novel Anti-NeuroOncology Drugs

“…The polyhalogenated pyridyl carbonates are neutral molecules that when coupled with lipids via high energy linkers -carbonates, phosphates, etc., fulfill the above requirements for novel high energy anticancer agents that could be attracted to and accumulate in CNS cancer tissue [16,[19][20][21]. The carbonate moiety like phosphate has the properties (resonance) of the high energy 3-atom moieties described in Fig.…”

“…Even the highly resistant IC implanted D54 glioma was sensitive to DM-CHOC-PEN. The drug has minimal toxicity and has encouraging potential [16,19,21]. …”

“…6, where DM-CHOC-PEN is proposed to be acting as a non-classical alkylating agent. The scheme describes a dual carbonium ion -DNA cross-linking mechanism (in a G-X-C sequence) with tumor DNA in the major groove via N 7 -guanine [20]. A bi-molecular coupled product (via the trichloromethylene group) has been identified as the major microsomal metabolite of PEN [20].…”

“…The scheme describes a dual carbonium ion -DNA cross-linking mechanism (in a G-X-C sequence) with tumor DNA in the major groove via N 7 -guanine [20]. A bi-molecular coupled product (via the trichloromethylene group) has been identified as the major microsomal metabolite of PEN [20]. The trichloromethylene group is required, since the dichloromethylene analog of PEN is not active [does not react with 4-(p-nitrobenzyl) pyridine (NBP] (Struck, personnel communication).…”

“…Each was homogenized in phosphate buffer, extracted with dichloromethane, and evaporated to dryness. The residues were assayed by HPLC and DM-CHOC-PEN, a guanine-N 7 -CCl 2 -adduct with DM-CHOC-PEN involving the -CCl 3 moiety and the DM-CHCO-PEN dimer-Cl 2 C-CCl 2 -were identified in the glioma tissue [16]. Neither DM-CHOC-PEN nor metabolites could be identified in the normal brain tissue.…”