Novel Structures of Uracil Mustard (Uramustine) Retaining Cytotoxic Activity and Drug-likeness for Oral Administration | Chapter 16 | New Insights into Disease and Pathogen Research Vol. 2
Aims:
To present 12 new variants of uracil mustard having drug-like properties and
cytotoxic functional group, by utilizing uracil mustard (uramustine) as a lead
compound. Utilize rigorous substructure and similarity of a molecular scaffold
to determine drug like variants. Physicochemical properties determined indicate
the variants have favorable drug-likeness.
Study Design: Conduct molecular
database search utilizing features of substructure and similarity based upon
uracil mustard.
Place and Duration of Study:
Department of Chemistry, Medicinal Chemistry Study Section, University of
Nebraska at Omaha, Omaha Nebraska between January 2015 to March 2015.
Methodology: Uracil mustard consists
of the pyrimidine derivative uracil, having the bifunctional nitrogen mustard
cytotoxic moiety covalently bonded onto the ring. A systematic search,
utilizing substructure component and similarity, within an in-silico database
search successfully determined 12 variants. Rigorous criteria for drug-likeness
were implemented to screen potential candidates that included the application
of the Rule of 5. In addition, maintaining the cytotoxic moiety of nitrogen
mustard was crucial.
Results: A total of 12 variants of
uracil mustard was identified after an extensive molecular database search
using rigorous criteria. All 12 variants, and including uracil mustard, showed
zero violations of the Rule of 5, thereby indicating favorable drug-likeness.
Values of polar surface area for all compounds at less than 80 Angstroms2
are suitable for central nervous system penetration. Polar surface area, number
of atoms, and Log P for all compounds increased as the molecular weight
increases. Structure substituents include nitrogen mustard groups, hydroxyl,
alkyl and carbonyl moieties. Cluster analysis discerned greatest similarity
among members of this group.
Conclusion: Applying rigorous search
criteria within a molecular data base, for comparison and reject, successfully
identified 12 variants of uracil mustard that show favorable drug-likeness in
addition to cytotoxic capability. The design of new antitumor agents is
important for increasing efficacy of the clinical treatment of cancer.
Variation of physicochemical properties can benefit the efficacy of anticancer
drugs and should be further investigated for the benefit of patients.
Author(s) Details
Dr. Ronald Bartzatt
Durham Science Center,
University of Nebraska, 6001 Dodge Street, Omaha, Nebraska 68182, USA.
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