Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain.
A 1, 4-dihydropyridine <--> pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. This concept was used in the present investigation as a model to deliver an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1, 4-dihydropyridine chemical delivery system (CDS) through an amide linkage. Five new-target compounds (23-27) of the 1, 4-dihydropyridine CDS type were synthesized through the reduction of five new pyridinium quaternary intermediates (18-22). The synthesized 1, 4-dihydropyridines were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies showed that 1-benzyl-3-[N-[2-bis(2-chloroethyl)aminoethyl]-carbamoyl]-1, 4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl ]carbamoyl]-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary compounds 18 and 22 respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies showed that compound 23 was able to cross the BBB at detectable concentrations. On the other hand, the in vitro alkylation activity studies revealed that 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl]carbamoyl]pyridinium bromide (22) is an alkylating agent with activity comparable to the known drug chlorambucil.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Magda A
MA
El-Sherbeny
Huda S
HS
Al-Salem
Maha A
MA
Sultan
Mahasen A
MA
Radwan
Hassan A
HA
Farag
Hussein I
HI
El-Subbagh
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004095:Dihydropyridines; D004337:Drug Carriers; C038806:1,4-dihydropyridine