University of Khartoum

Design by Synthesis and Biological Screening of Antitumor Anthracycline Aza-analogues; A Quantative Structure Activity Relationship (QSAR) Analysis Study

Design by Synthesis and Biological Screening of Antitumor Anthracycline Aza-analogues; A Quantative Structure Activity Relationship (QSAR) Analysis Study

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Title: Design by Synthesis and Biological Screening of Antitumor Anthracycline Aza-analogues; A Quantative Structure Activity Relationship (QSAR) Analysis Study
Author: Osman, Mohammed
Abstract: A training set of eleven known anthracyclines were picked from literature and some of their physiochemical parameters were calculated using semiempirical quantum mechanical methodsand correlated with their reported experimental biological activity data. These are the ID50values in vitroof the model anthracyclines against L1210 leukemia and two human colon tumour cell lines (Colon 4 and HT 29). Extensive statistical correlations between the physiochemical parameters (total energy,heat of formation, dipole moment and molecular refractivity) and ID50values were executed to yield about four hundred tables of paired data. The tableswhich give the highest r-values were chosen for further treatment. Thus two tables for each cell line were obtained, one represents one hour in vitroincubation and the other represents continuous incubation versus one of the calculated physiochemical parameters. Total energy parameters as calculated by AM1 and PM3 (used as such or transformed into their reciprocals) were found to give the highest linear correlation coefficients. Upon establishing a correlation between the physiochemical parameters and biological response (ID50), mathematical formulas were derived and used to calculate the anticipated biological responses of a designed set of hypothetical aza-analogue of the training set. This designed set contains three groups of aza-analogues of daunorubicin (15 compounds), aclarubicin (5 compounds) and rhodomycin (27 compounds). Physiochemical parameters of these aza-analogues were likewise calculated and used in aforementioned mathematical model to compute their biological activity data. Upon scrutiny, the calculated ID50values show very explicit and orderly trends which correlate well with calculated log P values of the designed set. The present QSAR model was found to be sensitive to the expected active cites in the designed set that are similar to those of the training set. Our set of designed anthracycline aza-analogues shows two uniform activity profile; one for both incubationsagainst Colon 4 and the other for both incubation against HT 29 cell lines while L1210 cell line partitioned between the two activity profile with one hour incubation mode lining up with Colon 4 and continuous incubation mode with HT 29. It also reveals that activity is directly proportional to lipophilicity for aza-daunorubicin and azarhodomycin groups while aza-aclarubicins exhibits the reverse behaviour. The most important outcome of this in silicomodel is the indication that the 2-N aza-analogues are generally more active than 1-N aza-analogue, a well-known behavior for aza-anthracenediones and aza-anthrapyrazoles hitherto unknown for anthracyclines.
Description: 189 Pages
URI: http://khartoumspace.uofk.edu/handle/123456789/8376
Date: 2015-04-07


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