Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity

In an attempt to synthesize potential anticancer agents acting by inhibitio n of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. Th e compounds were tested for their cytotoxic activity in vitro against H460 nonsmall lung carcinoma cell line, the activity being for 24 out of 37 comp ounds in the 0.01-0.3 muM range. A QSAR analysis indicated that lipophilici ty is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytot oxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaC l-mediated disruption of the ternary complex suggests that for the most pot ent compounds, e.g., 15, the cytotoxicity was at least in part related to s tabilization of the complex, as also supported by the persistence of the DN A-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of t he most potent analogue (15) was evaluated in direct comparison with topote can using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibit ion of tumor growth and rate of complete response.