**2. Materials and methods**

**1** was synthesized at DEKK-TEC as part of a series of polychlorinated pyridine carbonates and carbamates that are lipophilic, non-neurotoxic alkylators of human xenograft brain and breast

Anticancer activity for **1** has been well documented *in vivo vs.* IC implanted human xenograft glioblastoma (U-251 and D-54) and breast cancer (MX-1) mouse models at doses lower or equivalent to its LD10 [1-3]. Over 25 carbonate and carbamate analogs of **2** have been synthe‐ sized and evaluated *in vivo* and **1** was the most active of the analogs *vs.* the above IC implanted

X-ray crystallography studies with **1** describe a perfectly linear configuration (Fig. 2) that includes a neutral heterocyclic ring linked through a stable carbonate group to a lipophilic cholesteryl moiety [2]. These basic characteristics plus the neutralizing effects (electrophilic) of the polyhalogenated substitutions on the pyridine ring probably contribute to **1**'s ability to form micelle particles that penetrate the blood brain barrier, and accumulate in CNS tumor

A mechanism of action has been proposed for **1** that involves cross-linking across the trichlor‐

sequence [1]. This mechanism of action would allow **1** to be administered in combination with many of the clinically significant DNA major groove-alkylating drugs, that include methylat‐ ing agents [*e.g*. dacarbazine and temozolomide (TemodarR)] and chloroethylating agents [*e.g*. bis(chloroethyl)-nitrosourea (BCNU) and clomesone] – all of which form carbonium ion-

The pharmacokinetics, metabolic fate and toxicology of **1** in three animal species (mice, rats

Cognitive/behavioral studies have been conducted in rats and dogs and are reviewed in depth.




tumors implanted intracranially (IC) in mice [1-3].

240 Tumors of the Central Nervous System – Primary and Secondary

human xenograft cancer models [1-3].

**Figure 2.** Structural characteristics of **1**

mediated adducts *via O6*

and dogs) are reviewed here.

omethyl group with tumor DNA in the major groove *via N7*

tissues [1, 11].
