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 LogP, formula weight, and polar surface area for these compounds are: 1.554 to 3.52, 156.06 to 324.12, and 3.238 A2 to 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 silicosearch 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.

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