Utilizing a D-amino acid as a drug carrier for antineoplastic nitrogen mustard groups.
The evaluation of an alkylating nitrogen mustard agent that utilizes D-alanine as a drug carrier for three chloroethyl substituents (CICH2CH2-) is shown. Various important pharmacological properties were determined including polar surface area, partition coefficient, molar volume, polarizability, numbers of -OH and -NH2 groups, and aqueous solubility. The synthetic approach utilizes 1,2-dichloroethane reaction with the primary amine of D-alanine resulting in chloroethyl (CICH2CH2-) substituents. A nitrogen mustard group results, and this agent showed alkylation activity in aqueous solution directed toward a nucleophilic primary amine group. Kinetics of alkylation activity is determined by placing p-chloroaniline and the nitrogen mustard agent in sodium bicarbonate buffered aqueous solution at physiological pH 7.4 and 37 degrees C. Samples taken from the test solution are injected with fluorescamine that reacts specifically with primary amine functional groups. Absorbance measurements obtained at 400 nm by UV-Vis spectrometer indicates the relative amounts of nonalkylated p-chloroaniline in the test solution. The D-alanine nitrogen mustard agent effectively alkylated the nucleophilic primary amine of p-chloroaniline with zero-order kinetics. The rate constant was determined to be 7.445E-04 mol/l/min. Formula weight, polar surface area, Log P, molar volume, violations of Rule of 5 for D-alanine mustard agent are 276.59, 29.543 angstroms2, 1.605, 222.3 cm3, and zero violations, respectively. Cluster analysis of molecular properties showed D-alanine mustard agent to be quite similar to cyclophosphamide. This agent showed good druglikeness and zero violations of the Rule of 5, indicating good bioavailability. Molecular properties calculated for the mustard agent are numerically comparable to some clinical anticancer drugs.
Bartzatt
Ronald L
RL
University of Nebraska, Durham Science Center, Medicinal Chemistry Laboratory, Department of Chemistry, 6001 Dodge Street, Omaha, NE 68182, USA. bartzatt@mail.unomaha.edu
D000409:Alanine / Q000737:chemistry*; D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D016000:Cluster Analysis; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D012044:Regression Analysis; D013237:Stereoisomerism; D013678:Technology, Pharmaceutical / Q000379:methods
D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D009588:Nitrogen Mustard Compounds; D000409:Alanine