Novel Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors | Chapter: 5 | Modern Advances in Pharmaceutical Research Vol. 1
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 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.
Biography of author(s)
Ronald Bartzatt
University of Nebraska, College of Arts & Sciences,
Durham Science Center, 6001 Dodge Street, Omaha, Nebraska 68182, USA.
Read full article: http://bp.bookpi.org/index.php/bpi/catalog/view/47/233/398-1
View volume: https://doi.org/10.9734/bpi/mapr/v1
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