Antitumor Agents. 213. Modeling of Epipodophyllotoxin Derivatives Using Variable SelectionkNearest Neighbor QSAR Method

Abstract

We have applied a variable selection k nearest neighbor quantitative structure-activity relationship (kNN QSAR) method to develop predictive QSAR models for 157 epipodophyllotoxins synthesized previously in our ongoing effort to develop potential anticancer agents. QSAR models were generated using multiple topological descriptors of chemical structures, including molecular connectivity indices (MCI) and molecular operating environment descriptors. The 157 compounds were separated into several training and test sets. The robustness of QSAR models was characterized by the values of the internal leave one out cross-validated R2 (q2) for the training set and external predictive R2 for the test set. The significance of the training set models was confirmed by statistically higher values of q2 for the original data set as compared to q2 values for the same data set with randomly shuffled activities. kNN QSAR models were compared with those obtained with the comparative molecular field analysis method; the kNN QSAR approach afforded models with higher values of both q2 and predictive R2. One of the best models obtained from kNN analysis using MCI as descriptors provided q2 and predictive R2 values of 0.60 and 0.62, respectively. QSAR models developed in these studies shall aid in future design of novel potent epipodophyllotoxin derivatives.

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

“…In the 1 H-NMR spectra, the proton at C-4 of 4β-triazole-substituted compounds appears as a doublet at δ 5.9-6.3 ppm, usually with a coupling constant J 3,4 < 5.0 Hz, indicating a cis-relationship between H-3 and H-4. The formation of the triazole ring was confirmed by the resonance of its C 5" -H signal (δ 7.8-8.2 ppm) in the aromatic region in the 1 H-NMR spectra, which was further supported by two characteristic carbon signals at around 145 ppm and 126 ppm in the 13 C-NMR spectra. The coupling constant of the anomeric proton of the glucose residue (J 1"',2"' ) is typically <4.0 Hz for the α-linkage and >7.6 Hz for the β-linkage.…”

“…Click-chemistry strategy for the synthesis of 4β-triazole-linked glucose podophyllotoxin conjugates. All the products were characterized by 1 H-NMR, 13 C-NMR, ESI-MS, and HRESI-MS. In the 1 H-NMR spectra, the proton at C-4 of 4β-triazole-substituted compounds appears as a doublet at δ 5.9-6.3 ppm, usually with a coupling constant J 3,4 < 5.0 Hz, indicating a cis-relationship between H-3 and H-4.…”

“…The coupling constant of the anomeric proton of the glucose residue (J 1"',2"' ) is typically <4.0 Hz for the α-linkage and >7.6 Hz for the β-linkage. In addition, the anomeric carbon of an α-glucoside always has a lower chemical shift than the corresponding β-glucoside in the 13 C-NMR spectra. Poor water-solubility is a common problem in developing podophyllotoxin derivatives for therapeutic use.…”

“…Among them, five semisynthetic derivatives, etoposide (2), teniposide (3), etopophos (4), GL-331 (5) and TOP-53 (6) ( Figure 1) are currently used in the chemotherapy for a variety of cancers, including small-cell lung cancer, non-Hodgkin's lymphoma, leukemia, Kaposi's sarcoma, neurobslastoma and soft tissue sarcoma. These derivatives display binding activity to DNA topoisomerase II during the late S and early G2 cell cycle stages and are potent inhibitors of the enzyme [7][8][9][10][11][12][13][14]. Their anticancer activity proceeds through a mechanism of action entirely different from that of their parent compound podophyllotoxin (1).…”

4β-[4′-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

“…13 It has also been indicated in the literature that bulky substitution at the C-4 position of the podophyllotoxin usually enhances the cytotoxicity and DNA topoisomerase-II inhibition activity. [14][15][16][17][18][19] Similarly, the urea derivatives such as bis-aryl ureas have been most extensively investigated new chemical entities following the success of Sorafenib 20 for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. 21,22 More importantly, this class of urea derivatives have been found to be potent inhibitors of human DNA topoisomerase-I and II .…”