ABSTRACT
Herein, we describe the structure-activity relationship study of a new 3-aryl-8H-thieno[2,3-b]pyrrolizin-8-one series of antitubulin agents. The pharmacological results from the National Cancer Institute in vitro human disease oriented tumor cell line screening allowed us to identify compound 1d (NSC 676693) as a very efficient antitumoral drug in all cancer cell lines tested. This prompted us to define the structural requirements essential for this antiproliferative activity. Among all analogues synthesized in this study, compound 1o was the most promising, being 10-fold more potent than compound 1d. Its activity over a panel of nine tumoral cell lines was in the nanomolar range for all of the histological types tested, and surprisingly, the resistant KB-A1 cell line was also sensitive to this compound. Moreover, a flow cytometric study showed that L1210 cells treated by the most potent compounds were arrested in the G(2)/M phases of the cell cycle with a significant percentage of cells having reinitiated a cycle of DNA synthesis without cell division. This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies that led to a new prodrug chemical approach.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pyrroles/chemical synthesis , Pyrrolizidine Alkaloids/chemical synthesis , Tubulin Modulators , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Structure , Neoplasm Transplantation , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolizidine Alkaloids/chemistry , Pyrrolizidine Alkaloids/pharmacology , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A new type of ether of dihydroartemisinin containing cyano and aryl groups was prepared and tested for cytotoxicity to A549, P388, L1210 and HT29 cells using the MTT assay. 12k and 12l were the most cytotoxic compounds. 13 lacking the peroxy group showed a 1000-fold less potency than 12l. Similarly, the inactive compound 14 indicated that the position of cyano groups was also important. Flow cytometry data showed that the compounds caused an accumulation of P388 cells in the G(1)-phase of the cell cycle.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Ethers/chemical synthesis , Ethers/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Animals , Artemisia/chemistry , Drug Screening Assays, Antitumor , Flow Cytometry , G1 Phase/drug effects , HT29 Cells , Humans , Leukemia L1210/drug therapy , Leukemia L1210/pathology , Leukemia P388/drug therapy , Leukemia P388/pathology , Mice , Tetrazolium Salts , ThiazolesABSTRACT
BACKGROUND: The new olivacine derivative S 16020-2 (NSC-659687) has entered clinical trials on the basis of a marked antitumor activity in experimental models. Amongst the analogues which were synthesized to improve both therapeutic index and antitumor activity, the most active ones were those esterified on the 9-OH group such as S 30972-1, the glutaric acid monoester derivative. PURPOSE: To compare the pharmacological profile of S 30972-1 and S 16020-2 in vitro and in vivo and to investigate whether S 30972-1 could act as a prodrug of S 16020-2. METHODS: The two compounds were compared in vitro in terms of their activity in inhibiting cellular proliferation and perturbing the cell cycle and in vivo in terms of their antitumor activity in murine transplantable tumors and human orthotopic models. The plasma concentrations of S 16020-2 and S 30972-1 were determined in mice, in a comparative pharmacokinetic study after i.v. administration, using an HPLC assay. RESULTS: Although tumor cell proliferation and accumulation of cells in the G2 phase of the cell cycle were similarly affected by the two compounds after a continuous exposure (IC50 values of 30-50 n M), S 30972-1 was about tenfold less potent than S 16020-2 after short exposures. In vivo, S 30972-1 induced more long-term survivors than S 16020-2 among mice with Lewis lung carcinoma and sensitive or multidrug resistant P388 leukemias. The growth of Colon 38 carcinoma was slightly more inhibited by S 30972-1 than S 16020-2. In the more relevant human orthotopic models, using the optimal doses of each drug, 160 mg/kg S 30972-1 was significantly more active than 80 mg/kg S 16020-2 in the NCI-H460 lung carcinoma. The two compounds were significantly active in A549 lung carcinoma, moderately active in the NIH:OVCAR-3 ovary carcinoma and inactive in the NCI-H125 lung and DU145 prostate carcinomas. Pharmacokinetic study demonstrated that S 30972-1 is a prodrug of S 16020-2: the conversion was rapid and complete within 1 h of the administration of S 30972-1. CONCLUSIONS: The in vivo profile of these two compounds appeared very similar, although S 30972-1 exhibited globally a wider therapeutic index. The rapid conversion of S 30972-1 to S 16020-2 shows that S 30972-1 acts mainly as a prodrug of S 16020-2. This should be taken into account before considering S 30972-1 as a valuable back-up of S 16020-2.
