Design and Synthesis of Novel Breast Cancer Therapeutic Drug Candidates Based upon the Hydrophobic Feedback Approach of Antiestrogens.

Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC50: 0.09 µM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur-π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD.

Plasma asparaginase activity, asparagine concentration, and toxicity after administration of Erwinia asparaginase in children and young adults with acute lymphoblastic leukemia: Phase I/II clinical trial in Japan.

BACKGROUND: A phase I/II study of Erwinia asparaginase in Japanese children and young adults with acute lymphoblastic leukemia (ALL) was performed to investigate its activity and toxicity. PROCEDURE: Eligible patients were in remission and had developed allergy to Escherichia coli asparaginase. Erwina asparaginase was intramuscularly administrated on days 2, 5, 7, 9, 11, and 13. To measure the plasma l-asparagine concentration (PAC), amino acids were derivatized with Nα -(5-fluoro-2,4-dinitrophenyl)-l-leucinamide. RESULTS: Six consecutive patients completed the phase I study with 25,000 IU/m2 per dose without dose-limiting toxicity and 18 patients completed the phase II study with 25,000 IU/m2 per dose. Median age of 24 patients was 7.5 (range 2-16) years. The half-life of plasma asparaginase activity (PAA) was 16.9 ± 7.5 hr and the maximum PAA was 3.10 ± 1.47 IU/ml (n = 23, noncompartment model). PAA of 0.1 IU/ml or more was achieved in all 23 patients (100%) 48 hr and in 18 of 23 patients (78.3%) 72 hr after the first administration. During the 2-week study, 94.2% (65 of 69) of the 48-hr samples and 80.4% (37 of 46) of the 72-hr samples had PAA of 0.1 IU/ml or more. PAC less than 1.0 µM was achieved in 95.7% patients 48 and 72 hr after administration. PAC values in all the samples were greater than the limit of quantitation (0.0625 µM). Karnofsky performance status of all patients was good during the 2-week study. CONCLUSIONS: Erwinia asparaginase 25,000 IU/m2 per dose × six intramuscular administrations in 2 weeks was well tolerated, pharmacologically efficacious, and safe in Japanese patients with ALL/lymphoblastic lymphoma.