Cyphetrylin cytotoxic analogues (report II)

Abstract

Introduction. Search of active compounds among cyphetrylin analogues is one of prospective directions in synthesis of new compounds that have higher resistance to fermentation. The report I presented the synthesis of new cyphetrylin compounds with various functional substituents (thiazolidin, naphthyl, rimantadine, chlorophenacyl and cyphelin), their presence on the surface of tumor cells when binding to receptors would enhance the cytotoxic effect of modified cyphetrylin compounds on tumor. Objective. The study of anti-tumor activity of the synthesized analogues cyphetrylin modified by cytotoxic agents. Materials and methods. The research was carried out on the transplanted murine tumors: breast adenocarcinoma Ca-755 and melanoma B-16. Drug solutions were prepared ex tempore with the use of dimethylsulfoxide or ethanol diluted with saline to a concentration of 10 % and was administered to female mice-hybrids F1 (C57Bl/6 х DBA/2) daily subcutaneous injection in doses of 5, 10, 20 and/or 30 mg/kg for 5 days. The criteria of antitumor effect served the tumor growth inhibition (TGI, %) and the increase in lifespan (ILS, %) of test animals compared to the controlled. Results. Boc-Cys(Thp) - Phe-D-Trp-Lys(ClPhe) - Thr-OMe - pentapeptide modified by chlorophenacyl lysine at N c -group in a dose of 5 mg/kg on breast adenocarcinoma Ca-755showed a short-term antitumor effect directly after the end of the treatment (TGI = 73 %). Boc-Phe-D-Trp-Lys (Ac-Sar-Val) - Thr-OMe - tetrapeptide modified by cyphelin lysine at №-group in a dose of 10 mg/kg caused melanoma B-16 growth inhibition for 75-85 % within 4 days after the end of the treatment and increased lifespan (ILS) of mice for 29 %. Conclusion. 2 of 7 cyphetrylin analogues, modified by cytotoxic agents, showed antitumor activity, that indicate the prospects for their further research as antitumor compounds on other tumor models.