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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