Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters

Abstract

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their A-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/ breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone ;-H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone ;-H2AX could be used as a biomarker for the upcoming clinical trials of S39625. [Mol Cancer Ther 2007;6(12):3229 -38]

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

“…In accord, a recent study on the nature of ABCG2 interaction with camptothecin analogs has revealed a similar dependence on the presence of hydroxyl or amine groups on the outer ring of their common camptothecin structure, possibly facilitating hydrogen bond formation, essential for substrate recognition and efflux via ABCG2; these camptothecin positions seem to be analogous to the present R1, R2, or R3 positions of IAs (Yoshikawa et al, 2004). Several subsequent publications on ABCG2-dependent resistance to novel camptothecin analogs have also obeyed this general hydrogen bond rule (Rajendra et al, 2003;Bates et al, 2004;Takagi et al, 2007). Hence, these cumulative results emphasize the robustness of basic structural features of ABCG2 efflux substrates from diverse groups of polyaromatic cytotoxic agents.…”

Preclinical profile of antitumor activity of a novel hydrophilic camptothecin, ST1968

“…In conclusion, taking into account the difficulty to identify novel topoisomerase I inhibitors (4,37), the peculiar features of ST1968 may have obvious therapeutic implications in view of a possible clinical development. …”

Química e farmacologia de quimioterápicos antineoplásicos derivados de plantas

“…22 Outra maneira de estabilização do anel E é através da retirada do grupo lactônico, que bloqueia completamente a abertura do anel, assim como nos derivados cetônicos que também mantêm a alta atividade anti-TOP1. O derivado ciclobutano metilenodióxi, S39625 (12) está em fase pré-clínica avançada de desenvolvimento, 19,23,24 com resultados mais potentes que a camptotecina em testes com algumas linhagens de células cancerígenas. Outros derivados da camptotecina (13-15) são mostrados na Tabela 1.…”

“…Um exemplo pode ser a emodina, ou 1,3,8-tri-hidróxi-6-metilantraquinona (24), isolada do ruibarbo, Rheum palmatum L. (Polygonaceae), que inibe a caseína quinase-2 (CK2).…”