Structure‐Activity Relationship of Alkyl Camptothecin Esters

Abstract

The cytotoxicity of camptothecin (CPT) esters 1-6 was measured. Like parental camptothecin, esters 2 and 3, but not 1, 4, 5, and 6, inhibited proliferation of human leukemia cells in culture and induced programmed cell death as assessed by flow cytometry studies. Exhibition of similar levels of antiproliferative activities of CPT 2 and 3 required different incubation time periods in cell cultures, with CPT and 3 requiring the shortest and longest periods, respectively. Both 2 and 3 were inactive against cells resistant to the semisynthetic CPT derivative 9-nitrocamptothecin and unable to stabilize DNA-topoisomerase I (Topo I) "cleavable complexes" in a cell-free system, suggesting that Topo I activity was required but insufficient for the mechanism of action of 2 and 3. Mouse liver homogenate converted esters to parental CPT, but the conversion rates were different with different esters. Of four tested esters in this experiment, ester 2 had the fastest conversion rate. In vivo studies showed that ester 2 had an exceptional lack of toxicity in nude mice, even at enormous doses, and demonstrated extensive activity against human breast and colon tumors grown as xenografts in immunodeficient nude mice, whereas no antitumor activity was observed for the other esters. In conclusion, ester 2 is a prodrug of the antitumor compound CPT, and it can be administered at very high doses in mice with no appearance of toxicity. This study provides a basis for further evaluation of CPT ester 2 as an investigational anticancer agent.

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

“…In a subsequent study with 9-NC, the propanoate ester and butyrate esters showed the greatest toxicity in HL-60 cells and U-937 cells in vitro . 204 In vivo data using Doyle lung carcinoma, BRO-melanoma, SPA lung carcinoma and BRE stomach tumor xenografts also suggested promising antitumor activity, however, the poor solubility of the constructs prompted the investigators to dissolve the drugs in cottonseed oil and inject the solutions into the stomach cavity through the anterior wall of the abdomen everyday for five consecutive days each week for the duration of the experiment. While the compounds showed promising lactone stability and antitumor activity, the route of administration was not ideal for prolonged therapy.…”

Synthesis and antitumor activity of aromatic camptothecin esters

“…Using 9-nitrocamptothecin (0.5 g, 0.0013 mol), 3-fluorobenzoic acid (1 g, 0.0071 mol), DCC (1.5 g, 0.0073 mol), and DMAP (0.2 g, 0.0016 mol) as the starting materials, pure product 16 (0.6 g) was obtained as a yellow powder, yield 90%, purity 99%. 1 [17]. Using 9-nitrocamptothecin (0.5 g, 0.0013 mol), 4-fluorobenzoic acid (1 g, 0.0071 mol), DCC (1.5 g, 0.0073 mol), and DMAP (0.2 g, 0.0016 mol) as the starting materials, pure product 17 (0.15 g ) was obtained as a yellow powder, yield 22%, purity 99% (HPLC).…”

“…The SAR studies with our synthetic 20-acyl camptothecin derivatives showed that all alkyl esters had low toxicity, and that their antitumor activities varied depending on the property of their side ester chains (16,17). Only compounds with a straight C 2 or C 3 alkyl ester chain were found to be active; the remainder were either slightly active or not active at all.…”

Development and validation of a reverse-phase HPLC with fluorescence detector method for simultaneous determination of CZ48 and its active metabolite camptothecin in mouse plasma

“…CZ48 has demonstrated strong anticancer activity against human tumor xenografts in nude mice with an exceptional lack of toxicity. CZ48 acts as a prodrug and exerts its anticancer activity by CE mediated hydrolysis to the active metabolite CPT in vivo [11].…”