SPECIFIC BRAIN DELIVERY OF PYRIDYL CHLOROETHYLUREA DERIVATIVES AS POTENTIAL ANTITUMOR AGENTS: SYNTHESIS, EVALUATION AND MOLECULAR MODELING STUDY

摘要

The present investigation describes the synthesis; evaluation and molecular modeling studies of a series of 1 -substituted-1,4-dihydropyridine-3-chloroethylurea derivatives IIIa-e as potential agents for treatment of brain tumors. The incorporation of the 1,4-dihydropyridine moiety in the structure attains an efficient site specific chemical delivery system (CDS) of the chloroethylurea (CEU) as a known antitumor pharmacophore to the brain. The target compounds IIIa-e were synthesized through reduction of the corresponding quaternary compounds IIa-e. The in-vitro oxidation studies showed that, compounds IIIa-e could be oxidized into their corresponding quaternary compounds IIa-e, respectively which attains their "locked in" characteristics as brain antitumor agents. The in-vivo studies showed that compound IIIa was able to cross the BBB at detectable concentration. In addition the in-vitro alkylating activity studies using 4-(4-nitrobenzyl)pyridine (NBP) revealed that compound IIe is an efficient alkylating agent with activity comparable to reference drug chlorambucil. The target compounds were tested for their binding to the colchicine-binding site (CBS) of beta-tubulin using Molecular Operating Environment (MOE) software.