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-OCO 2 -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 1 o and 2 o 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.