Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity

Abstract

Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.

Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

“…To determine further the conservation between yeast and human in the DNA damage checkpoint and demonstrate the relevance of the ATM pathway to current cancer therapy, we compared the capacities of ATM-pro®cient (MRC-5) and ATM-de®cient (AG04405) human ®broblasts to survive after treatments with topotecan and gradiation. Topotecan is an anticancer drug that transforms topoisomerase I-DNA transient intermediates into lethal DNA lesions, and has been suggested to activate a DNA damage checkpoint (Ryan et al, 1994;Kingsbury et al, 1991). Both ATM+/+ and ATM7/7 cells were treated with increasing concentrations of topotecan (0.02 ± 3 mM) and their viability was measured as explained in Materials and methods.…”

“…As topotecan can activate a DNA damage checkpoint (Ryan et al, 1994;Kingsbury et al, 1991), its eect on activation of Chk2 was investigated. Also, to determine whether Chk2 is activated in response to (7).…”

Topoisomerase I inhibitors and drug resistance

“…Other camptothecins are under development, including 9-aminocamptothecin and 9-nitrocamptothecin (Wani et al, 1980;Kingsbury, 1991;Pantazis et al, 1992) and other analogs (Wang et al, 1994;Valenti et al, 1997;Zhao et al, 1997). Some authors have described lipid formulations of camptothecin which display in vivo the capacitty to concentrate in the gastrointestinal tract (Sugarman, 1996).…”

Development of Guanidine-Bisurea Bifunctional Organocatalyst Bearing Chirality at the Inner and Outer Sides of the Urea Groups, and Application to Enantioselective α-Hydroxylation of Pyranoindolizine Intermediate for Camptothecin Synthesis

“…To date, two camptothecin analogues, i.e., irinotecan (2) [6][7][8][9] and topotecan (3) [10][11][12], have been approved by the FDA to treat cancers. Structurally, CPTs contain a pyranoindolizine tricyclic structure (the C-D-E ring system) with a tert-hydroxyl group at C20, and the stereochemistry at C20 is important…”