Novel Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors

Introduction: Brain and spinal cord tumors are the third most common type of child hood cancer, with
only leukemia and lymphoma having greater frequency. Cancers that occur in the central nervous
system (CNS) can be primary (tumors that begin in the CNS) and metastatic (tumors formed from
cancer cells beginning in other parts of the body).
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 identified
drug 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. A set of eleven novel drug structures are elucidated by in silico optimized
substituent search that is founded on the successful anticancer nitrogen mustard scaffold of
mechlorethamine. Brain metastases have been linked to breast cancer, advanced melanoma, and
colorectal cancer. Various molecular properties that enable the transition from blood to CNS have
been identified and found to be optimal for the twelve agents reported here. The Log P numerical
values fall between 1.554 to 3.52 which is arrange well within the BBB piercing range of 1.0 to 4.00. In
addition the values of PSA range from 3.238 to 22.24 Angstroms2, which is a range well below the
upper limit for effective CNS penetration at 90 Angstroms2. Importantly all twelve agents present zero
violations of the Rule of 5, indicating a high level of drug-likeness and favorable bioavailability. The
success rate of in silico search and identification of suitable CNS targeting antineoplastic structures
was less than ten percent. Various attributes recounting the inherit potential of small molecules
applied as chemotherapeutic agents in the treatment of CNS tumors.