Synthesis of aromatic nitrogen mustard agents and analysis of their alkylation activity at physiological pH and temperature.
A Structure Activity Relationship (SAR) study was accomplished with six aromatic compounds which have a nitrogen mustard (N-mustard) substituent. N-mustard agents are very important for the clinical treatment of many types of cancers. All N-mustard agents synthesized alkylated a nucleophilic primary amine (p-chloroaniline) in aqueous solvent at pH 7.4 and 37 degrees C. Rate constants and rate equations were determined for the alkylation reactions by monitoring the formation of a fluorescent complex formed when fluorescamine complexes the unreacted p-chloroaniline. Fluorescamine complexation of the unreacted primary amine halts the alkylation reaction and allows the determination of remaining unreacted primary amine, which in turn permits the determination of rate constants and rate equations. The fluorescamine-amine complex shows a strong absorbance peak at a wavelength of 400 nanometers in aqueous solvent. The molar absorptivity (epsilon) was calculated to be 18.37 L/(mole x cm). First order rate constants ranged from 0.513E-2 minute(-1) to 1.32E-2 minute(-1) with second order rate constants from 2.85E-2 (M x minute)(-1) to 4.78E-2 (M x minute)(-1). The aromatic compounds included benzoic acid, m-chlorobenzoic acid, hydrocinnamic acid, m-toluic acid, and 3,4-dimethoxybenzoic acid. The synthesis procedure produced the N-mustard agents at > or = 90% yield and high purity. Partition coefficient Log(Kow)Log P values ranged from 2.66 to 4.18. The N-mustard agents consisted of greyish-yellow crystals which retained alkylation activity for more than ten weeks when stored at -10 degrees C and were soluble in water at 25 degrees C and 37 degrees C.
Bartzatt
Ronald
R
University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, Omaha, Nebraska 68182, USA.
Kasher
Laura
L
D000478:Alkylation; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013696:Temperature
D006841:Hydrocarbons, Aromatic; D009588:Nitrogen Mustard Compounds