Abstract
The impact of lipophilicity as represented by the logarithm of octanol/water partition coefficient (logP), the combined steric/polarizability effect as represented by molar refractivity (MR) and bulk as represented by molar volume (MV) on the biological activity of 29 known aminopyrimidoisoquinolinequinones APIQ were analyzed using quantitative structure activity relationships methodology (QSAR). The activity data chosen was the inhibitory concentration (IC50) against human gastric adenocarcinoma (AGS) cell line. On running regression analysis, the physicochemical parameters and IC50 show very weak correlations as evident by the low values of Pearson Correlation R2 (0.1 to 0.2). Since the individual compounds show appreciable activity (ranging from 20 to 0.5 μM), classification was resorted to in order to expose mechanistic nesting subgroups. This was done by clustering data points around various trend lines extracted from the scattered plot relating parameters to activity using R2 as an index. The correlation of IC50 versus MV was chosen a base of classification owing to higher statistical metrics it yield. This gave five regression lines, each of which is believed to represent a separate mechanistic profile. Additional descriptors were used to consolidate the clustering approach and to give depth to the assumed mechanistic profiles of each cluster.
Highlights
The quinone moiety has been showed to possess anticancer activity and numerous cancer drugs in clinical use contain this unit since the discovery of daunorubicin and adriamycin in 1960’s [1] [2] [3]
In this paper we study the activity of APIQ’s in attempt to expose mechanistic aspects via Quantitative structure-activity relationships (QSAR) mythology
1) Regression analysis of log P, molar refractivity (MR), molar volume (MV) and their combination versus IC50 Biological activity data was first curated by removing problematic data points
Summary
The quinone moiety has been showed to possess anticancer activity and numerous cancer drugs in clinical use contain this unit since the discovery of daunorubicin (daunomycin 1a) and adriamycin (doxorubicin 1b) in 1960’s [1] [2] [3]. They belong to anthracycline class of compounds which are featured by anthracene-9,10-dione chromophore to which is fused a six-membered alicyclic ring with a carbethoxy group at C9 and a sugar moiety at C7 [5] These compounds are naturally occurring antibiotic isolated from cultures of streptomyces species [2]. Angucyclinones 5a are aromatic polyketides and naturally occurring biologically active angular benz (a) anthrathene-9,10-dione derivatives [15] They look like the anthracyclines in that they are naturally occurring isolated from numerous strains of Streptomyces [16], in addition to their derivation from the same chromophore. Linear regression and regression clustering are used in the present study to extract information about predictive ability and about hidden mechanistic trends of a data set of 29 known aminopyrimidoisoquinolinequinones (APIQ’s)
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