A bifunctional alkylating nitrogen mustard agent that utilizes barbituric acid as carrier drug with the potential for crossing the brain-blood barrier.
Barbituric acid is the parent compound of a large family of hypnotic barbiturates. A nitrogen mustard (N-mustard) group (-CH2CH2N[CH2CH2Cl]2) was placed onto the two nitrogen atoms at positions 1 and 3 of the pyrimidine ring. This N-mustard agent is a solid at 25 degrees C, stable at -10 degrees C for >10 weeks, and soluble in aqueous solvent at 37 degrees C and 25 degrees C. The partition coefficients miLog P and CLog P were calculated to be -0.93 and -1.441 for barbituric acid. The miLog P and CLog P for the N-mustard agent were 1.82 and 2.707, respectively. The N-mustard substituents significantly increased solubility in lipid by-layers. The N-mustard agent alkylated a nucleophilic primary amine (p-chloroaniline) at physiological conditions of pH 7.4 and 37 degrees C. Aliquots of reaction mixtures were withdrawn at known time periods to react with fluorescamine for determination of unreacted p-chloroaniline and calculation of rate constants. The alkylation of the primary amine was second order with rate = k2[Nu]2, (Nu is nucleophile) and rate constant k2 = 0.01358 L/(mole.min). The molecular dipole of barbituric acid and the N-mustard agent was calculated by SPARTAN software (wavefunction, Irvine, CA) to be 0.681 and 2.153 Debye, respectively. The brain/blood partition coefficient (Log BB) of the N-mustard agent was -0.399. Values of molecular polar surface area (TPSA) for barbituric acid and the N-mustard agent was 75.27 and 64.17, respectively. TPSA values indicate an expected intestinal absorbance to be 79% and 90%, respectively. The N-mustard agent showed zero violations of the Rule of 5, indicating good bioavailability.
Bartzatt
Ronald
R
University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, Omaha, Nebraska 68182, USA. bartzatt@mail.unomaha.edu
Donigan
Laura
L
D001463:Barbiturates / Q000737:chemistry / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D007700:Kinetics; D013058:Mass Spectrometry; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
D001463:Barbiturates; D009588:Nitrogen Mustard Compounds; C032232:barbituric acid