Design and synthesis of etoposide-related topoisomerase II inhibitors by conventional and computational approaches

Etoposide (1) and teniposide (2) are DNA topoisomerase II (topo II) inhibitors that have been used in front-line cancer chemotherapy since the 1980s. Problems associated with 1 and 2 include acquired drug-resistance, poor water-solubility, and metabolic inactivation. To circumvent the aforementioned problems, three series of analogs were designed, synthesized, and evaluated for activity in causing cellular protein-linked DNA breakage as well as cytotoxicity against KB and 1-resistant KB/7d cells. Molecular modeling studies were incorporated to formulate useful structure-activity relationships (SAR) and guide rational optimization of this compound class.; Several quantitative SAR (QSAR) methods, including comparative molecular field analysis (CoMFA), q2 Guided Region Selection (q2-GRS), and k Nearest Neighbor (kNN) QSAR, were used to generate QSAR models for 157 epipodophyllotoxins. Robust models with consistently high q2 and predictive R2 values were provided by the kNN-QSAR technique. Pharmacophore modeling of four diverse topo II inhibitors was also attempted with the HipHop module implemented in Catalyst. These models, in combination with prior SAR and conventional drug design approaches, directed the synthetic efforts.; C₄ modification using different linkages (p-carbonyl anilino, p-amino anilino, amino, and carbonyl) extended with protected amino acids was intended to optimize activity and modulate water-solubility simultaneously. Eight compounds (6–11, 15–16) induced more protein-linked DNA breaks than 1, with two of them (9 and 16) superior to GL 331, a novel 4β-arylamino analog currently in phase II clinical trials. The preliminary metabolism and toxicity studies of selected compounds encourage further development and analog synthesis following this molecular design.; C_4′ esterification was introduced to improve the water-solubility of this compound class. The esterified derivatives retained the superior activity and drug-resistance profiles of the parent compounds.; D-ring enol ether variation was designed to eliminate the C₂ epimerization and hydrolysis metabolic pathways. Rudimentary chemistry of this modification was explored.