st-1481 and homocamptothecin

Topoisomerase I (TopoI), an essential enzyme, produces a DNA single strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential transesterifcations. The breakage and closure reactions generate phosphodiester bonds and similar free energies, so the reaction is freely reversible. The TopoI reaction intermediate consists of enzyme covalently linked to DNA dubbed a 'cleavable complex'. Covalently bound TopoI-DNA complexes can be recovered. Camptothecin analogs, topotecan and irinotecan, are approved TopoI-targeted drugs. Both have limitations due to the equilibrium between the camptothecin lactone and ring-opened forms. Several strategies are being explored to develop improved TopoI inhibitors. Homocamptothecins, in which the metabolically labile camptothecin lactone is replaced with a more stable seven-membered beta-hydroxylactone, are potent anticancer agents. Gimatecan is a seven-position modified lipophilic camptothecin developed to provide rapid uptake and accumulation in cells and a stable TopoI-DNA-drug ternary complex. Diflomotecan, a homocamptothecin, and gimatecan are in Phase II clinical trial. Among non-camptothecins, edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins, is in Phase II clinical trial. Indenoisoquinolines were identified as TopoI inhibitors by the NCI 60-cell line COMPARE analysis. Co-crystal structures of two indenoisoquinolines with TopoI-DNA elucidated the structure of the ternary complex. Indenoisoquinolines are in preclinical development. Dibenzonaphthyridinone TopoI inhibitors have undergone extensive structure-activity examination. ARC-111 was selected for in-depth preclinical study. Biomarkers are under investigation to predict clinical efficacy from preclinical models, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from TopoI inhibitor therapy. gamma-H2AX formation may be a useful pharmacodynamic marker. A gene signature developed for topotecan sensitivity/resistance may have value in patient identification. Convergence of these efforts should result in clinically effective second generation TopoI inhibitors.

Topics: Animals; Antineoplastic Agents; Biomarkers; Camptothecin; Carbazoles; Humans; Indenes; Indoles; Isoquinolines; Naphthyridines; Topoisomerase I Inhibitors

In contrast to five-membered E-ring analogues, 7-oxyiminomethyl derivatives of homocamptothecins showed ability to form stable ternary complexes with DNA and topoisomerase I. The 7-oxyiminomethyl derivatives of homocamptothecins were evaluated as a racemic mixture. Following the isolation of the two enantiomers, the 20 (R)-hydroxy isomer confirms the best activity. By using a panel of human tumor cells, all tested homocamptothecins showed a potent antiproliferative activity, correlating to the persistence of the cleavable complex. No significant difference was observed between the natural scaffold and the corresponding homocamptothecin homologue. A selected compound of this series exhibited an excellent antitumor activity against human gastrointestinal tumor xenografts.

Topics: Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Stereoisomerism; Structure-Activity Relationship; Xenograft Model Antitumor Assays