New acetylenic derivatives of betulin and betulone, synthesis and cytotoxic activity

Abstract

Betulin 1 and its semisynthetic derivatives exhibit a cytotoxic activity toward various cancer cell lines. These compounds are a promising and potential anticancer candidates. A series of betulin derivatives was prepared and tested for the antiproliferative activity in vitro against T47D breast cancer, CCRF/CEM leukemia, HL-60 promyelocytic leukemia, SW707 colorectal, murine P388 leukemia, as well as BALB3T3 normal fibroblasts cell lines. Cisplatin and betulin 1 were used as a reference compounds. Some derivatives of betulin showed a higher cytotoxic activity than the parent compound 1. Two derivatives (5 and 17) were 24-fold potent than betulin 1 against the human promyelocytic leukemia cell line (HL-60), with an IC₅₀ value of 0.3 µg/mL.

Keywords: Betulin; Betulone; Cytotoxic activity; Lipophilicity; Synthesis.

Fig. 1

Chemical structure of betulin 1 and betulone 2

Scheme 1

Synthesis of derivatives 3–26. Reagents and conditions: a RCOOH, CH₂Cl₂, DCC, DMAP, rt, 24 h or ROC(O)Cl, benzene, pyridine, rt, 24 h; b PCC, CH₂Cl₂, rt, 2 h