Alkylation activity and molecular properties of two antineoplastic agents that utilise indometacin and a conjugate of aspirin with 2-aminonicotinic acid to transport nitrogen mustard groups.
BACKGROUND
Nitrogen mustard (N-mustard) compounds are considered important anticancer drugs. Various transporting agents have been utilised to carry N-mustard groups including coumarins, amides, polyaromatic molecules and cycloalkyl structures. N-mustards act as bifunctional alkylating agents that induce cross-linking within DNA strands and cytotoxic activity. Compounds that transport the N-mustard group in vivo can also express drug-likeness that can have advantages in clinical application. This study presents data on two anticancer drugs with N-mustard groups covalently attached to NSAIDs.


METHODS
Two alkylating compounds were synthesised by covalently attaching a single N-mustard group to 2-2-acetoxybenzoylaminonicotinic acid (for compound I) and indometacin (for compound II). Molecular properties such as aqueous solubility, 1-octanol/water partitioning coefficient (log Kow), molar volume, polar surface area, 1-octanol/water partitioning at pH values other than human blood (log D) and the dermal permeability coefficient (Kp) were determined. The rate-order of reaction and rate constant of alkylation were determined by reacting compound I and compound II with a target compound having a primary amine group in buffered aqueous solution at blood pH 7.4 and 37 masculineC, and monitoring absorbance at 400nm. RESULTS AND C onclusion: Compounds I and II were stable at room temperature, soluble in water and effectively alkylated a nucleophilic primary amine target at physiological temperature and pH. The water solubility of compound I was considerably greater than that of compound II. Both compounds showed second-order rate order of alkylation and effectively alkylated a nucleophilic target under aqueous physiological conditions of pH 7.4 and 37 masculineC. Kp values for compounds I and II were determined to be 0.000786 cm/h and 0.024 cm/h, respectively. Both compound I and compound II had zero percent ionisation at pH 7.4, and compound I showed zero violations of the Rule of 5. Log P values for compounds I and II were 3.27 and 5.08, respectively. This study describes the benefits of antineoplastic agents with NSAID substituents that provide favourable pharmacological properties.
Bartzatt
Ronald
R
Chemistry Department, University of Nebraska, Omaha, NE 68182, USA. bartzatt@mail.unomaha.edu
D000478:Alkylation; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001241:Aspirin / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D006868:Hydrolysis; D007202:Indicators and Reagents; D007213:Indomethacin / Q000737:chemistry*; D008466:Mechlorethamine / Q000737:chemistry*; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000737:chemistry*; D012869:Skin Absorption; D012984:Software
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018906:Antineoplastic Agents, Alkylating; D007202:Indicators and Reagents; D009539:Nicotinic Acids; D008466:Mechlorethamine; C110415:2-aminonicotinic acid; D001241:Aspirin; D007213:Indomethacin