Measuring the Alkylation Kinetics and Drug Likeness of Four Novel Antineoplastic Compounds | Chapter 05 | Advances in Applied Science and Technology Vol. 4

Aims: To synthesize small molecule alkylating compounds and analyze the kinetics of the alkylation in aqueous solution. Determine molecular properties and the drug likeness of these four compounds as  potential  antineoplastic  agents  and  apply  statistical  analysis  to  identify  interrelationships  of properties.

Study  Design: Four  compounds  were  synthesized,  characterized,  and  studied  for  alkylation capability.  The  alkylation  kinetics was elucidated,  as  well  as  drug  likeness  properties.  The interrelationships of properties were examined by statistical methodology.

Place  and  Duration  of  Study: Department  of  Chemistry,  Durham  Science  Center,  University  of Nebraska at Omaha, Omaha NE, from May 2015 to June 2015.

Methodology: Four compounds were modified by the covalent bonding of an alkyl halide substituent or nitrogen mustard group. The four compounds were placed in aqueous solution at pH 7.4 and 37°C to  monitor  alkylation  efficiency  that  targeted  p-chloroaniline.  Alkylation  was  monitored  utilizing fluorescamine  and  measurement  at  400  nm.  Time  and  absorbance  plots  determined  whether alkylation step is first-order or second-order. Molecular properties Log P, formula weight, polar surface area, etc., were determined. Statistical analysis and path analysis revealed which molecular property was most responsible for rate constant values.

Results: Compounds A, B, C, and D showed ranges of Log P, formula weight, and polar surface area of  0.010  to  4.21,  177.59  to  714.77,  and  29.64  to  88.63,  respectively.  All  compounds  showed  a favorable drug likeness, with only compound C showing a violation of the Rule of 5. The Log P values and number of alkylation reactive sites were most responsible for rate constant value.

Conclusion: Small molecule alkylating agents are synthesized, the efficiency of alkylation measured in aqueous solution utilizing fluorescamine at pH 7.4 and 37°C. Rate-order of reactions is determined utilizing  fluorescamine  assay  for  surviving  primary  amine  groups.  The  four  compounds  showed  a favorable drug likeness based on molecular properties.

Author(s) Details

Dr. Ronald Bartzatt

University of Nebraska, Durham Science Center, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

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