DHA-SB-T-1213

Cytotoxic activity of 47 semi-synthetic Taxoteres against four different cancer cell lines, such as ovarian cancer (A121), human colon adenocarcinoma (HT29), human breast cancer (MCF7) and drug-resistant human breast cancer (MCF7R), was used to develop a quant. structure-cytotoxicity relationship (QSCR).The data were divided into training (38) and test sets (9), in which the former was used to develop the QSCR and the later was used for the prediction of three of the cell lines namely A121, HT29 and MCF7.In the case of MCF7R, the training set contained 36 compounds and the test set contained nine compoundsThe statistical measures such as squared correlation coefficient (r² = 0.73-0.81), adjusted squared correlation coefficient (r² adj = 0.72-0.80), cross-correlation coefficient (q² = 0.62-0.75) and F-ratio (17.49-27.49) were found to be satisfactory.Other statistical diagnoses such as n/p ratio, fraction of the variance in terms of r² and quality factor (Q) were also satisfactory.Thermodn., lipophilic/hydrophilic, spatial (Jurs descriptors) and topol. (Kier and Hall connectivity indexes) descriptors contributed to the activity.Functional groups required at R₁-R₃ positions for enhanced activity are discussed.The developed QSCR models can be used in the design and development of newer semi-synthetic Taxotere derivatives for the cancer therapy.

Although taxanes such as paclitaxel and docetaxel are the two most important clinically available anticancer drugs for the treatment of various cancers (including colon cancer), the success of these two drugs has been tempered by the development of various unbearable side effects as well as multi-drug resistance. Therefore, it is essential to search new taxane analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for colon cancer patients. In this paper, four series of taxane derivatives were used to correlate their inhibitory activities against colon cancers mainly with the hydrophobic and steric descriptors of their substituents in order to gain a better understanding of their chemical-biological interactions. QSAR results from this paper have suggested that the steric and hydrophobic parameters of the substituents are the two most important determinants for the activities of taxane analogues (under consideration) against colon cancers, with a major contribution coming from the molar refractivity of the substituents. Statistical diagnostics, internal validation, and external validation tests have validated all the QSAR models.