In Silico Optimized Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors

Aims: Brain and spinal cord tumors are the third most common type of childhood cancer following leukemia and lymphoma. Mechlorethamine (or mustine) is a nitrogen mustard antineoplastic drug. Eleven variants of mechlorethamine are presented that possess molecular properties enabling substantial access to tumors of the central nervous system.
Study Design: An extensive in silico search within a data library of molecular structures identifieddrug scaffolds suitable for targeting brain tumors.
Place and Duration of Study:University of Nebraska, Durham Science Center, Department of Chemistry, Omaha, Nebraska 68182 USA, between July 2012 to December 2012.
Methodology: Following extensive in silico search and identification of potential drug structures, a conclusive set of brain penetrating structures were compiled. Extensive characterization of structure properties was accomplished followed by multivariate numerical analysis utilizing pattern recognition and statistical analysis.
Results: All twelve compounds (including mechlorethamine) exhibited zero violations of Rule of 5, indicating favorable bioavailability. The range in Log P, formula weight, and polar surface area for these compounds are: 1.554 to 3.52, 156.06 to 324.12, and 3.238 A2to 22.24A2,respectively. High resolution hierarchical cluster analysis determined that agent 2 and 6 are most similar to the parent compound mechlorethamine. The average Log P, formula weight, polar surface area, and molecular volume are 2.446, 235.433, 8.58 A2, and 213.8 A3, respectively.
Conclusion: These eleven drug designs possess attributes that effectuate high permeation into the central nervous system.