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Current Trends in Medicinal Chemistry   Volumes    Volume 7 
Computer aided drug design of nitrogen mustard agents for treatment of chronic lymphocytic leukemia (CLL)
Ronald Bartzatt
Pages: 1 - 10
Number of pages: 10
Current Trends in Medicinal Chemistry
Volume 7 

Copyright © 2013 Research Trends. All rights reserved

Chronic lymphocytic leukemia (CLL), or B-cell chronic lymphocytic leukemia (B-CLL), is the most common type of human leukemia. Although CLL is considered a disease of adults, it can occur in teenagers and children. Twenty-seven nitrogen mustard agents are formulated by in silico structural searches based on similarity to a clinically successful anticancer agent bendamustine with focus on substituent mining. The outcome are nitrogen mustard constructs having pharmaceutical properties (i.e. Polar surface area, Log P, formula weight) suitable for good bioavailability, favorable intestinal absorption, and acknowledged cytotoxic activity. The numerical ranges for Log P and polar surface area for all 27 agents including bendamustine are: 1.943 to 5.39, and 33.429 A2 to 95.662 A2, respectively. Twenty-six of the derivatives to bendamustine showed zero violations of the Rule of 5, indicating these agents will have effective bioavailability and druglikeness. A total of nine pharmaceutical properties were determined for all compounds, with the numerical values found to be highly correlated (Pearson r > 0.9000). Hierarchical cluster analysis of all molecular properties revealed that bendamustine is analogous to all derivatives, save for the agent having one violation of the Rule of 5. Analysis of similarity (ANOSIM) of these same descriptors determined an ANOSIM r statistic of 0.1375, indicating high similarity among members of the group. All structures of the new derivatives preserve the alkylating moiety of the nitrogen mustard cytotoxic (-N(CH2CH2Cl)2) construct, which includes intra-strand and inter-strand cross-linking of the DNA strand. Altogether the diversity of Log P and polar surface area properties of these anticancer agents contribute significantly to enhanced bioavailability and thereby greater versatility in antitumor action.
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