Alkylation activity and multivariate analysis of the molecular properties of four antineoplastic agents that utilize a D-amino acid, citric acid, 1-octanol, or 4-oxoazetidine-2-carboxylic acid to transport alkylating groups

Nitrogen (N)-mustard agents are the most widely utilized anticancer drugs and are used for the treatment of leukemias and solid tumors. Compounds utilized to carry these alkylating groups include coumarins, amides, polyaromatic molecules, and cycloalkyl structures. These alkylating agents can induce monoalkylation of DNA strands, which causes single-strand breaks in DNA for cytotoxic action. N-mustards may act as bifunctional agents that can induce cross-linking within DNA strands as their cytotoxic activity. Novel structures that transport the N-mustard group can express enhanced drug-likeness, which has advantages in clinical application. Four alkylating compounds were synthesized utilizing 4-oxoazetidine-2-carboxylic acid (compound I), D-alanine (compound II), citric acid (compound III), or 1-octanol (compound IV) as the framework. The resulting products formed monofunctional (I and IV) or polyfunctional (II and III) alkylating compounds. Various important molecular properties, such as aqueous solubility, log octanol-water partition coefficient (log Kow), molar volume, polar surface area (PSA), dermal permeability coefficient (Kp), and rate-order of reaction and rate constant of reaction were determined. Multivariate methods, such as cluster analysis and principal coordinates analysis, were used to analyze the molecular properties of these compounds and determine similarities and dissimilarities. Multivariate methods were used to discern relationships among this complex group of compounds. All four compounds were stable at room temperature, soluble in water, and effectively alkylated a nucleophilic primary amine target at physiological temperature and pH. Compounds I, II, and IV are predicted to be >90% absorbed in the intestinal tract and compound III >60% absorbed. Analysis via Rule of 5 indicates that compounds I, II, III, and IV are expected to show effective bioavailability and permeation. Compounds I, II, and IV will effectively penetrate the blood-brain barrier (BBB) based upon PSA values. Water solubilities of compounds I, II, III, and IV decrease as the value of log Kow increases. Values of molar refractivity, molar volume, and parachor increase as molecular weight increases. Multivariate analysis showed that compounds II and IV are highly similar and indicated that these compounds could have analogous clinical applications. Compound I is predicted to have potential antibacterial activity due to a β-lactam ring, in addition to effective alkylation activity. Compound II resists hydrolyzing-enzyme esterases due to the D-amino-acid structure. Compound III is a polyfunctional-alkylating agent that would inhibit mitosis as an adjunct to DNA cross-linking. Compound IV has a single methanesulfonate group providing monoalkylation of suitable nucleophilic sites. PSA and log Kow values indicate effective penetration of the BBB by compounds I, II, and IV. Rule of 5 analysis showed that compounds I, II, III, and IV would have effective bioavailability. All compounds effectively alkylated a nucleophilic target under aqueous physiological conditions of pH 7.4 and 37°C. This work demonstrates the benefits of designing antineoplastic agents with novel molecular structures that provide favorable pharmacological properties.