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Alkylphosphocholines as Promising Antitumor Agents: Exploring the Role of Structural Features on the Hemolytic Potential
Author(s) -
de Sá Matheus Malta,
Pasqualoto Kerly Fernanda Mesquita,
Modestia Silvestre Massimo,
RangelYagui Carlota O.
Publication year - 2014
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201300124
Subject(s) - hemolysis , chemistry , alkyl , cationic polymerization , stereochemistry , ring (chemistry) , structure–activity relationship , combinatorial chemistry , in vitro , biochemistry , organic chemistry , immunology , biology
Alkylphosphocholines (APC) are promising antitumor agents, which have the cellular membrane as primary target; however, red blood cell damage limits their wide therapeutic use. A variety of APC analogs has been synthesized and tested showing less hemolytic effect than the class prototype, Miltefosine (HePC). In this work, chemometric methods were applied to a set of 34 APC derivatives to identify the most relevant structural and molecular features of hemolytic activity. The APC derivatives were divided into three groups: (i) N ‐methylpiperidine and N ‐methylmorpholine derivatives with a long alkyl chain or flexible cyclopentadecyl rings, displaying a hemolytic rate of 17 %; (ii) adamantyl and cyclopentadecyl derivatives, showing an average hemolysis of 39 %; and, N,N,N ‐trimethylammonium, trans ‐ N , N , N ‐trimethylcyclohexanamine, and trans ‐ N , N , N ‐trimethylcyclopentanamine derivatives, whose average hemolysis was 41 %. The findings suggested that the presence of either bulky cationic head groups, or rings such as adamantyl and cyclohexyl, primarily increases the hemolysis of compounds with eleven atoms in the alkyl chain. Moreover, the macrocyclic cyclopentadecyl seems to be important to the hemolytic potential especially of compounds with five carbon atoms in the alkyl chain. Regarding linear carbon chain derivatives with no ring substitution, less bulky cationic head groups seem to favor hemolysis. Thus, in order to design more potent and less toxic APC antitumors, the reported structural/molecular patterns should not be included in their structure.