Anticancer activities of carbonate and carbamate derivatives of 4-demethylpenclomedine

A280 4-DM-PEN is a non-neurotoxic metabolite of penclomedine (PEN) with anti-cancer properties. However, 4-DM-PEN does not readily cross the blood brain barrier and does not produce complete remissions in intracerebral (IC) gliomas. PEN did produce responses in clinical trials (gliomas - CR), but was neurotoxic and all trials ceased. DEKK-TEC and SRI have synthesized 20 carbonate and carbamate derivatives of 4-DM-PEN. Analogs prepared were from the series: 4-DM-PEN-4-OCO2-X & 4-DM-PEN-4-OCONH-X, where X = benzyl, methyl, ethyl, octyl, 4-Cl-, 4-F-, 4- & 2-nitrobenzyl, phenyl, 4-Cl-, 4-F-, 4-nitrophenyl, N-morpholino and cholesteryl groups. Anti-cancer activities were noted with both groups when administered IP daily x 5 days to SC growing MX-1 xenografts [response ranges - %ILS >50% and 20-40% CR]. However, only a carbonate, 4-demethyl-4-cholesteryloxy-penclomedine (DM-CHOC-PEN, X=cholesteryl) was active (produced CRs) vs. three IC implanted xenograft tumor (U251, D54 & MX-1) models with no weight loss. BCNU controls did not produce CRs in IC implanted glioma xenografts, such as D-54 in mice. The IC tumor responses for DM-CHOC-PEN are the platform for our interest in evaluating the latter drug as clinical treatment for 1o and 2o CNS malignancies in humans. The IC activity is in contrast to DM-PEN, which was active vs. MX-1 breast tumor xenografts growing SC in mice but did not produce CRs in IC implanted human U-251and D-54 glioblastoma multiforme xenografts and MX-1 xenograft models. DM-CHOC-PEN vs DM-PEN has improved activity (% ILS/CR) in IC implanted human xenograft models - U251 glioma: +29/25 vs 17/0, resp. and MX-1 breast cancer: +20/17 vs 12/0, resp. DM-CHOC-PEN’s acute toxicology in mice and dogs has been reported - AACR 48, abst. 5614, 2007. Mechanisms for CNS anticancer activity and clinical plans for Phase 1 trials will be discussed. Supported by NCI/SBIR grant - 5R44CA85021.